Therese Sørlie

• Lien, Torbjørn Amundsen; Dhakal, Sushil; Wium, Anne Marthe Fosdahl; Bergholtz, Helga; Gunesten, Serhat & Flatekvål, Helene Midtun [Vis alle 11 forfattere av denne artikkelen] (2026). FGFR1 Suppresses STING-Mediated Interferon Response in Endocrine Therapy-Resistant Breast Cancer. Cancer Research Communications. 6(9), s. 2220–2231. doi: 10.1158/2767-9764.CRC-25-0821. Fulltekst i vitenarkiv
• Chmelova, Lucia; Davies, Helen R.; Degasperi, Andrea; Rinaldi, Giuseppe; Wils, Leon & Black, Daniella [Vis alle 55 forfattere av denne artikkelen] (2026). High-depth whole genome sequencing of premalignant breast lesions reveals rearrangement hotspots and personalized management opportunities. Nature Communications. 17(1). doi: 10.1038/s41467-026-72952-1. Fulltekst i vitenarkiv Vis sammendrag

  Ductal carcinoma in situ is a non-obligate precursor lesion of breast cancer. Often detected by mammography, most cases are managed through surgical and/or radiotherapy approaches. Today, it is not possible to predict which patients will progress to invasive disease. Here, we evaluate high-depth whole-genome sequenced ductal carcinoma in situ, enriched for high-grade clinical lesions, to understand whether deep WGS could reveal biological insights and/or personalized therapeutic vulnerabilities that may be targetable. We find genomic locations that are likely susceptible to producing the initiating lesion for structural variations prone to subsequent evolution, termed SHOREs. We additionally highlight individualized therapeutic potential that would otherwise not be appreciable without whole genome sequencing. We posit that holistic whole genome sequencing profiling could offer a more precise stratification approach, discerning higher-risk cases for prospective clinical studies on personalized therapies, from truly low-risk cases suitable for active monitoring.

• Redondo-Pedraza, Jaime; Santamaría, Patricia G.; Sanchez-Juan, Alejandro; Jimenez, María; Rocha, Ana Sofia & Soria-Alcaide, Gonzalo [Vis alle 21 forfattere av denne artikkelen] (2026). Rank signaling drives basal cell-lineage infidelity leading to mammary tumorigenesis. Nature Communications. 17. doi: 10.1038/s41467-026-70020-2. Fulltekst i vitenarkiv Vis sammendrag

  Rank signaling regulates mammary gland development and epithelial differentiation. While Rank is expressed in both basal and luminal cells, its basal-specific role is unclear. Here, using inducible basal-specific Rank expression and lineage tracing, we show that Rank signaling regulates basal cell identity in postnatal mammary glands. Increased basal Rank activity disrupts basal and luminal identities, causing aberrant luminal-like differentiation, lactation defects, and premalignant lesions composed of hybrid basal-derived cells that progress to basal and luminal adenocarcinomas. Conversely, Rank loss reduces tumor formation and also impairs cell identity. Mechanistically, proteomic, transcriptomic, and chromatin analyses reveal that Rank activation drives epigenetic remodeling, leading to basal identity loss and tumor initiation. A basal Rank gene signature correlates with ductal carcinoma in situ recurrence, as well as poor outcomes in luminal breast cancers. Thus, basal Rank-driven lineage infidelity promotes pre-invasive lesions and transition to invasive breast cancer in females.

• arozamena, Carlos Casas; Lande, Karin Teien; Diaz, Eva; Vilar, Ana; Cueva, Juan & Arias, Efigenia [Vis alle 16 forfattere av denne artikkelen] (2026). Longitudinal circulating tumor DNA profiling in patients with advanced endometrial cancer using an off-the-shelf targeted NGS panel. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.70246. Fulltekst i vitenarkiv
• Wang, Shixiong; Santacana-Font, Gemma; Kedra, Darek; Gilfillan, Siv; Tena-Chaves, David & Bergholtz, Helga [Vis alle 13 forfattere av denne artikkelen] (2025). The harmonized activities of HER2–HER3 heterodimer and deacetylated FOXA1 evade hormone response by regulating FOXA1 chromatin binding. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(20). doi: 10.1093/nar/gkaf1086. Fulltekst i vitenarkiv Vis sammendrag

  FOXA1 is a key transcription factor that mediates the effects of estrogen receptor (ER) and HER2 signaling in breast cancer. However, the mechanisms underlying FOXA1 regulation by HER2 and ER remain poorly understood. Here, we investigated FOXA1 regulation in cells with varying HER2 levels and its impact on endocrine therapy response. Chromatin interaction analyses revealed that high HER2 levels enhance FOXA1 binding to chromatin regions while reducing ER occupancy. Mechanistically, FOXA1 is acetylated by the histone acetyltransferase EP300 at the WD1 domain in ER-positive cells, attenuating its DNA binding at HER2-induced chromatin regions. Conversely, FOXA1 deacetylation—triggered by HER2/HER3 activation—increases its binding to ER-independent regions and promotes insensitivity to hormone therapy. In a luminal breast cancer patient-derived xenograft model, HER2/HER3 signaling increased FOXA1 chromatin binding and reduced sensitivity to ER-targeted treatment. We identify HDAC2 as a key deacetylase modulating FOXA1 acetylation and partially mediating the effects of HER2/HER3 signaling. Altogether, our findings highlight the significance of FOXA1 acetylation, regulated by the HER2/HER3–HDAC2–FOXA1 axis, in controlling FOXA1 chromatin binding and shaping breast cancer progression and therapy response. These insights may inform future therapeutic strategies.

• Lindemann, Kristina Yvonne Kathe; Kildal, Wanja; Kleppe, Andreas; Tobin, Kari Anne Risan; Pradhan, Manohar & Mascialino, Barbara [Vis alle 11 forfattere av denne artikkelen] (2025). Real-world outcomes in molecular subgroups for patients with advanced or recurrent endometrial cancer treated with platinum-based chemotherapy. International Journal of Gynecological Cancer. ISSN 1048-891X. 35(5). doi: 10.1016/j.ijgc.2024.101618. Fulltekst i vitenarkiv Vis sammendrag

  Objective There is scarce real-world evidence on patients with advanced/recurrent endometrial cancer treated with platinum-based chemotherapy. We assessed the oncological outcome in groups by molecular classification. Methods This retrospective cohort study included patients with advanced/recurrent endometrial cancer treated with platinum-based chemotherapy after hysterectomy at The Norwegian Radium Hospital, Oslo University Hospital, Norway, between January 2006 and December 2017. Patients were molecularly classified as pathogenic POLE mutated, mismatch repair deficient, p53 abnormal, or no specific molecular profile. Time-to-recurrence and cancer-specific survival were calculated. Results We identified 264 advanced-stage patients (stage III/IV) and 96 patients with recurrent disease. The molecular classification was prognostic for time-to-recurrence (p < .0001) and cancer-specific survival (p < .0001) in patients with advanced disease, but the outcome did not differ significantly by molecular groups in recurrent patients. In all molecular groups, patients with stage III disease had longer time-to-recurrence and cancer-specific survival compared to patients with stage IV disease. The worst outcome was observed in patients with p53 abnormal tumors with an HR of 1.57 (95% CI 1.07 to 2.30) for time-to-recurrence and HR of 1.78 (95% CI 1.19 to 2.65) for cancer-specific survival in stage III/IV disease and an HR of 1.45 (95% CI 0.83 to 2.52) for time-to-recurrence and HR of 1.60 (95% CI 0.99 to 2.68) for cancer-specific survival in patients with recurrent disease. The few patients with POLE mutated tumors had favorable outcomes despite the advanced/recurrent disease status. Conclusions Oncological outcomes differ by molecular groups, in particular among patients with advanced disease. Patients with p53 abnormal tumors have the worst outcome, while patients with POLE mutated tumors have favorable outcomes even with recurrent disease. Implementation of the addition of immunotherapy to chemotherapy is expected to lead to substantial improvement of outcome, particularly in patients with mismatch repair deficient advanced/recurrent disease. There is still a high unmet need in advanced/recurrent patients with p53 abnormal and no specific molecular profile tumors.

• Fjørtoft, Marit Otterlei; Garred, Øystein; Lingjærde, Ole Christian; Johannesen, Karin Teien; Ottestad, Lars & Bergheim, Inger Riise [Vis alle 29 forfattere av denne artikkelen] (2025). Single-cell analysis reveals tumour size as a key driver of immune cell profile alterations in primary breast tumours and corresponding lymph nodes. BJC Reports. 3(1). doi: 10.1038/s44276-025-00152-3. Fulltekst i vitenarkiv Vis sammendrag

  At diagnosis, 30–40% of women with breast cancer have metastases in sentinel (SN) or axillary lymph nodes (ALN). Nodal status is a strong prognostic factor and guides treatment decisions. Immune checkpoint inhibition has shown some efficacy, which can increase in the neoadjuvant setting. A better understanding of how tumour cells in primary tumours and metastatic lymph nodes shape the local immune microenvironment may provide clues for more individualized therapeutic interventions. Methods We conducted deep immunophenotypic analysis of 29 primary breast tumours and 36 lymph nodes from 38 patients with primary operable breast cancer. Results The immune profile of the primary tumour was not predictive of the lymph node immune profile or metastatic status. Primary tumours showed prominent CD8 T cell exhaustion and activated regulatory T cells, and the frequencies of these subsets were associated with tumour size. The immune cell profile in lymph nodes were different from the profile in primary tumours, except for the ALN+ nodes, which displayed a T-cell profile more similar to primary tumours. The frequencies of the T cell subsets in lymph nodeswere associated with metastatic size. Tumour cells from smaller metastases exhibited a distinct phenotype compared to those from larger tumour deposits, and the size of the tumour cell deposit impacted the local immune cell composition. Conclusion The tumour size of primary tumours and metastatic size in lymph nodes are the main drivers of changes in immune cell composition

• Clarke, Robert B. & Sørlie, Therese (2025). A Guide to Breast Cancer Research: An Introduction. Advances in Experimental Medicine and Biology. ISSN 0065-2598. 1464, s. 1–5. doi: 10.1007/978-3-031-70875-6_1. Fulltekst i vitenarkiv
• Bergholtz, Helga; Norum, Jens Henrik; Lien, Tonje Gulbrandsen; Skrede, Martina; Garred, Øystein & Sørlie, Therese (2025). B cells and energy metabolism in HER2-positive DCIS: insights into breast cancer progression from spatial-omics analyses. Breast Cancer Research. ISSN 1465-5411. 27(1). doi: 10.1186/s13058-025-01990-2. Fulltekst i vitenarkiv Vis sammendrag

  During breast tumor progression, the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step with large implications for prognosis. However, the mechanisms of invasion are still largely unknown. At the DCIS stage, there is an over-representation of HER2-positive lesions compared with invasive breast cancer. In this study, we investigated the associations between gene expression profiles in cancer cells and the immune microenvironment of HER2-positive DCIS and invasive breast tumors with concurrent DCIS using spatial transcriptomics. We found distinctly more B cells in the vicinity of DCIS ducts than in invasive tumor areas. There was higher expression of genes involved in energy metabolism in DCIS cancer cells than in invasive cancer cells and a positive correlation between expression of metabolic genes and B-cell abundance in DCIS. In contrast were processes related to epithelial to mesenchymal transition negatively correlated with B-cell abundance in DCIS. We also found significant correlation between expression of the B-cell-attracting chemokines CCL19, CCL21 and CXCL13 in stromal cells and B cell abundance in DCIS. This study indicates that B cells may play a protective role in the progression of HER2-positive DCIS to invasive breast cancer and that increased metabolic activity in intraductal cancer cells in combination with chemokines produced by stromal cells may influence the immune microenvironment of DCIS. These findings have implications for understanding HER2-positive breast cancer progression.

• Lindemann, Kristina Yvonne Kathe; Siegenthaler, Franziska; Johannesen, Karin Teien; Arozamena, Carlos Casas; Nebdal, Daniel Johan Hammer & Rau, Tilman T. [Vis alle 13 forfattere av denne artikkelen] (2025). Prognostic value of assessing ctDNA in patients with endometrial carcinoma - an international multicenter study. Gynecologic Oncology. ISSN 0090-8258. 195, s. 98–105. doi: 10.1016/j.ygyno.2025.03.002. Fulltekst i vitenarkiv Vis sammendrag

  Objective: At present, no reliable blood-based biomarkers have been established for patients with endometrial cancer. Liquid biopsies, which can detect circulating tumor DNA (ctDNA), provide a non-invasive way to assess prognosis, monitor tumor evolution and treatment response. We aimed to examine the feasibility and performance of ctDNA as a prognostic tool in a multi-center cohort of EC patients with matched tumor samples. Methods: Blood plasma samples were collected preoperatively from 83 patients at three European cancer centers. Circulating cell-free DNA (cfDNA) was isolated and analyzed using the Oncomine™ Pan-Cancer cell-free assay. Tumor tissue from 56 of the 83 patients was subjected to whole-exome sequencing, and clinical data were collected for oncological outcome assessment. Results: The mean input of cfDNA was 8.17 ng (range 1.47–29.12 ng). Sixteen (19.3 %) patients were considered ctDNA positive with mutations in one or more genes. Most alterations detected in plasma were concordant with mutations found in the matched tumor for the paired cases. The preoperative presence of ctDNA was associated with a significantly higher rate of recurrence (37.5 % vs 11.9 %, P = 0.024). Although eight of the 14 (57 %) patients with recurrence were negative for ctDNA at diagnosis, positive ctDNA status remained an independent predictor of recurrence also when controlling for other known histopathologic risk factors (HR 5.49, 95 % CI 1.5–20, P = 0.010). Conclusions: Our results demonstrated the feasibility of using an off-the-shelf gene panel to detect ctDNA in patients with endometrial cancer. ctDNA positivity was significantly associated with worse oncological outcomes.

• Moragas, Núria; Fernandez-Nogueira, Patricia; Recalde-Percaz, Leire; Inman, Jamie L.; López-Plana, Anna & Bergholtz, Helga [Vis alle 15 forfattere av denne artikkelen] (2024). The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma. Breast Cancer Research. ISSN 1465-5411. 26(1). doi: 10.1186/s13058-024-01871-0. Fulltekst i vitenarkiv
• Sharma, Abhibhav; Debik, Julia; Naume, Bjørn; Ohnstad, Hege Oma; Sahlberg, Guro Kristine Kleivi & Borgen, Elin [Vis alle 25 forfattere av denne artikkelen] (2024). Comprehensive multi-omics analysis of breast cancer reveals distinct long-term prognostic subtypes. Oncogenesis. 13(1), s. 1–13. doi: 10.1038/s41389-024-00521-6. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.

• Kildal, Wanja; Cyll, Karolina Urszula; Kalsnes, Joakim; Islam, Rakibul; Julbø, Frida Marie Ihle & Pradhan, Manohar [Vis alle 35 forfattere av denne artikkelen] (2024). Deep learning for automated scoring of immunohistochemically stained tumour tissue sections – Validation across tumour types based on patient outcomes. Heliyon. 10(13), s. 1–19. doi: 10.1016/j.heliyon.2024.e32529. Fulltekst i vitenarkiv Vis sammendrag

  We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9–98.5 %) for the nuclear model, 85.6 % (73.3–96.6 %) for the cytoplasmic model, and 78.4 % (75.5–84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.

• Davidson, Ben; Lande, Karin Teien; Nebdal, Daniel J.H.; Nesbakken, Anne Jorun; Holth, Arild & Lindemann, Kristina Yvonne Kathe [Vis alle 8 forfattere av denne artikkelen] (2024). Endometrial carcinomas with ambiguous histology often harbor TP53 mutations. Virchows Archiv. ISSN 0945-6317. 0(0), s. 1–9. doi: 10.1007/s00428-024-03912-7. Fulltekst i vitenarkiv Vis sammendrag

  The objective of the present study was to characterize the molecular features of endometrial carcinomas with ambiguous histology. Eighteen carcinomas that could not be conclusively typed based on morphology and immunohistochemistry underwent analysis of mismatch repair (MMR) status, microsatellite status, and whole-exome sequencing. None of the tumors had pathogenic POLE mutation. Twelve tumors (67%) were microsatellite stable, and 6 (33%) had microsatellite instability. Fourteen tumors (78%) harbored TP53 mutations, and 2 (11%) had mutations in MMR genes. Eleven carcinomas (61%) were classified as copy number high and 7 (39%) as MSI-hypermutated, the latter including 3 tumors with TP53 mutation who concomitantly had MSI or mutation in a MMR gene. Other mutations that were found in > 1 tumor affected MUC16 (7 tumors), PIK3CA (6 tumors), PPP2R1A (6 tumors), ARID1A (5 tumors), PTEN (5 tumors), FAT1 (4 tumors), FAT4 (3 tumors), BRCA2 (2 tumors), ERBB2 (2 tumors), FBXW7 (2 tumors), MET (2 tumors), MTOR (2 tumors), JAK1 (2 tumors), and CSMD3 (2 tumors). At the last follow-up (median = 68.6 months), 8 patients had no evidence of disease, 1 patient was alive with disease, 8 patients were dead of disease, and 1 patient died of other cause. In conclusion, based on this series, the molecular landscape of endometrial carcinomas with ambiguous histology is dominated by TP53 mutations and the absence of POLE mutations, with heterogeneous molecular profile with respect to other genes. A high proportion of these tumors is clinically aggressive.

• Ohnstad, Hege Oma; Blix, Egil Støre; Akslen, Lars Andreas; Gilje, Bjørnar; Raj, Sunil Xavier & Skjerven, Helle [Vis alle 45 forfattere av denne artikkelen] (2024). Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer—a prospective national multicentre study (EMIT-1). ESMO Open. 9(6), s. 1–12. doi: 10.1016/j.esmoop.2024.103475. Fulltekst i vitenarkiv Vis sammendrag

  Background EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. Patients and methods Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians’ treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. Results Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). Conclusion The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

• Cun, Han T.; Bernard, Laurence; Lande, Karin Teien; Lawson, Barrett C.; Nesbakken, Anne Jorun & Davidson, Ben [Vis alle 11 forfattere av denne artikkelen] (2024). Comprehensive molecular characterization of early stage grade 3 endometrioid endometrial adenocarcinoma. Gynecologic Oncology. ISSN 0090-8258. 189, s. 138–145. doi: 10.1016/j.ygyno.2024.07.677. Fulltekst i vitenarkiv Vis sammendrag

  Objective The treatment for stage IB grade 3 endometrioid endometrial adenocarcinoma is challenging with variable practice. Molecular characterization may help identify adjuvant therapy strategies beyond stage. We aimed to better understand the molecular features of these tumors by characterizing them by ProMisE classification, mutational signature, and commonly mutated genes. Methods Patients with stage IB grade 3 EEC at two institutions were included. Immunohistochemistry and whole exome sequencing were performed on archival FFPE tissue sections to determine ProMisE classification. Personal Cancer Genome Reporter was used for somatic variant annotation, and mutational signatures were generated based on COSMIC single base substitution mutational signatures. Results 46 patients were included with variable adjuvant treatment. Nine patients recurred (19.6%), most with extra-abdominal disease (n = 5, or 55.6%). 10 had POLE mutations (21.7%), 18 were MMR deficient (39.1%), 6 had abnormal p53 (13.0%), and 12 were p53 wildtype (26.1%). There were no recurrences in the POLE subgroup. A dominant mutational signature was identified in 38 patients: 17 SBS5 signature (44.7%), 10 SBS15 or SBS44 signature (26.3%), 7 SBS10a or SBS10b signature (18.4%), 3 SBS14 signature (7.9%), and 1 SBS40 signature (2.6%). The six patients that recurred had a SBS5 signature. Frequently mutated genes included ARID1A (n = 30, 65%), PTEN (n = 28, 61%), MUC16 (n = 27, 59%), and PIK3CA (n = 25, 54%). Conclusions This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches.

• Polec, Anna; Ekstrøm, Per Olaf; Fougner, Christian; Sørlie, Therese & Norum, Jens Henrik (2023). Rapid assessment of 3-dimensional intra-tumor heterogeneity through cycling temperature capillary electrophoresis. BMC Research Notes. 16. doi: 10.1186/s13104-023-06437-5. Fulltekst i vitenarkiv Vis sammendrag

  Objective Tumors are heterogeneous three-dimensional masses populated by numerous cell types, including distinct sub-clones of cancerous cells. Various sub-clones within the same tumor mass may respond differently to cancer treatment, and intra-tumor heterogeneity contributes to acquired therapeutic resistance. Thus, one tissue biopsy will in most cases not be representative of the entire genetic landscape of a tumor mass. In this study, we aimed to establish an easily accessible, low cost method to address intra-tumor heterogeneity in three dimensions, for a limited number of DNA alterations. Results This study includes analyses of the three-dimensional (3D) distribution of DNA mutations in human colon cancer and mouse mammary gland tumor tissue samples. We used laser capture microdissection for the unbiased collection of tissue in several XY-planes throughout the tumor masses. Cycling temperature capillary electrophoresis was used to determine mutant allele frequency. High-resolution distribution maps of KRAS and Trp53 mutations were generated for each XY-plane in human and mouse tumor samples, respectively. To provide a holistic interpretation of the mutation distribution, we generated interactive 3D heatmaps giving an easily interpretable understanding of the spatial distribution of the analyzed mutations. The method described herein provides an accessible way of describing intra-tumor heterogeneity for a limited number of mutations.

• Amerongen, Renée van; Bentires-Alj, Mohamed; Boxtel, Antonius L. van; Clarke, Robert B.; Fre, Silvia & Suarez, Eva Gonzalez [Vis alle 13 forfattere av denne artikkelen] (2023). Imagine beyond: recent breakthroughs and next challenges in mammary gland biology and breast cancer research. Journal of mammary gland biology and neoplasia. ISSN 1083-3021. 28(1). doi: 10.1007/s10911-023-09544-y. Fulltekst i vitenarkiv Vis sammendrag

  Abstract On 8 December 2022 the organizing committee of the European Network for Breast Development and Cancer labs (ENBDC) held its fifth annual Think Tank meeting in Amsterdam, the Netherlands. Here, we embraced the opportunity to look back to identify the most prominent breakthroughs of the past ten years and to reflect on the main challenges that lie ahead for our field in the years to come. The outcomes of these discussions are presented in this position paper, in the hope that it will serve as a summary of the current state of affairs in mammary gland biology and breast cancer research for early career researchers and other newcomers in the field, and as inspiration for scientists and clinicians to move the field forward.

• Figlioli, Gisella; Billaud, Amandine; Ahearn, Thomas U.; Antonenkova, Natalia N.; Becher, Heiko & Beckmann, Matthias W. [Vis alle 114 forfattere av denne artikkelen] (2023). FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women. European Journal of Human Genetics. ISSN 1018-4813. 31(5), s. 578–587. doi: 10.1038/s41431-022-01257-w. Fulltekst i vitenarkiv Vis sammendrag

  Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07–2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08–1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs

• Haugen, Mads; Gythfeldt, Hedda von der Lippe; Egeland, Eivind Valen; Normann, Lisa Svartdal; Pandya, Abhilash D. & Vedin, Lise-Lotte [Vis alle 15 forfattere av denne artikkelen] (2023). Liver X receptors induce antiproliferative effects in basal-like breast cancer. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.13476. Fulltekst i vitenarkiv Vis sammendrag

  Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple-negative breast cancer. In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose-dependent decrease in tumor cell proliferation in estrogen receptor-positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal-like breast cancer model (in combination with carboplatin). Functional proteomic analysis identified differences in protein expression between responding and nonresponding models related to Akt activity, cell-cycle progression, and DNA repair. Furthermore, pathway analysis suggested that the LXR agonist in combination with carboplatin inhibits the activity of targets of E2F transcription factors and affects cholesterol homeostasis in basal-like breast cancer.

• Bergholtz, Helga; Lien, Tonje Gulbrandsen; Lingaas, Frode & Sørlie, Therese (2022). Comparative analysis of the molecular subtype landscape in canine and human mammary gland tumors. Journal of mammary gland biology and neoplasia. ISSN 1083-3021. s. 171–183. doi: 10.1007/s10911-022-09523-9. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Breast cancers in humans belong to one of several intrinsic molecular subtypes each with different tumor biology and different clinical impact. Mammary gland tumors in dogs are proposed as a relevant comparative model for human breast cancer; however, it is still unclear whether the intrinsic molecular subtypes have the same significance in dogs and humans. Using publicly available data, we analyzed gene expression and whole-exome sequencing data from 158 canine mammary gland tumors. We performed molecular subtyping using the PAM50 method followed by subtype-specific comparisons of gene expression characteristics, mutation patterns and copy number profiles between canine tumors and human breast tumors from The Cancer Genome Atlas (TCGA) breast cancer cohort (n = 1097). We found that luminal A canine tumors greatly resemble luminal A human tumors both in gene expression characteristics, mutations and copy number profiles. Also, the basal-like canine and human tumors were relatively similar, with low expression of luminal epithelial markers and high expression of genes involved in cell proliferation. There were, however, distinct differences in immune-related gene expression patterns in basal-like tumors between the two species. Characteristic HER2-enriched and luminal B subtypes were not present in the canine cohort, and we found no tumors with high-level ERBB2 amplifications. Benign and malignant canine tumors displayed similar PAM50 subtype characteristics. Our findings indicate that deeper understanding of the different molecular subtypes in canine mammary gland tumors will further improve the value of canines as comparative models for human breast cancer.

• Bjørklund, Sunniva; Aure, Miriam Ragle; Häkkinen, Jari; Vallon-Christersson, Johan; Kumar, Surendra & Evensen, Katrine Bull [Vis alle 34 forfattere av denne artikkelen] (2022). Subtype and cell type specific expression of lncRNAs provide insight into breast cancer. Communications Biology. 5(1), s. 1–14. doi: 10.1038/s42003-022-03559-7. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Long non-coding RNAs (lncRNAs) are involved in breast cancer pathogenesis through chromatin remodeling, transcriptional and post-transcriptional gene regulation. We report robust associations between lncRNA expression and breast cancer clinicopathological features in two population-based cohorts: SCAN-B and TCGA. Using co-expression analysis of lncRNAs with protein coding genes, we discovered three distinct clusters of lncRNAs. In silico cell type deconvolution coupled with single-cell RNA-seq analyses revealed that these three clusters were driven by cell type specific expression of lncRNAs. In one cluster lncRNAs were expressed by cancer cells and were mostly associated with the estrogen signaling pathways. In the two other clusters, lncRNAs were expressed either by immune cells or fibroblasts of the tumor microenvironment. To further investigate the cis-regulatory regions driving lncRNA expression in breast cancer, we identified subtype-specific transcription factor (TF) occupancy at lncRNA promoters. We also integrated lncRNA expression with DNA methylation data to identify long-range regulatory regions for lncRNA which were validated using ChiA-Pet-Pol2 loops. lncRNAs play an important role in shaping the gene regulatory landscape in breast cancer. We provide a detailed subtype and cell type-specific expression of lncRNA, which improves the understanding of underlying transcriptional regulation in breast cancer.

• Staaf, Johan; Häkkinen, Jari; Hegardt, Cecilia; Saal, Lao H.; Kimbung, Siker & Hedenfalk, Ingrid [Vis alle 25 forfattere av denne artikkelen] (2022). RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer. NPJ breast cancer. 8:94(1), s. 1–17. doi: 10.1038/s41523-022-00465-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set. We trained SSPs for subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for biomarkers from histopathology. Classifications were compared with Prosigna in two external cohorts (ABiM, n  = 100 and OSLO2-EMIT0, n  = 103). Prognostic value was assessed using distant recurrence-free interval. Agreement between SSP and NC for PAM50 (five subtypes) was high (85%, Kappa = 0.78) for Subtype (four subtypes) very high (90%, Kappa = 0.84) and for ROR risk category high (84%, Kappa = 0.75, weighted Kappa = 0.90). Prognostic value was assessed as equivalent and clinically relevant. Agreement with histopathology was very high or high for receptor status, while moderate for Ki67 status and poor for Nottingham histological grade. SSP and Prosigna concordance was high for subtype (OSLO-EMIT0 83%, Kappa = 0.73 and ABiM 80%, Kappa = 0.72) and moderate and high for ROR risk category (68 and 84%, Kappa = 0.50 and 0.70, weighted Kappa = 0.70 and 0.78). Pooled concordance for emulated treatment recommendation dichotomized for chemotherapy was high (85%, Kappa = 0.66). Retrospective evaluation suggested that SSP application could change chemotherapy recommendations for up to 17% of postmenopausal ER+/HER2-/N0 patients with balanced escalation and de-escalation. Results suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level and that SSP models can be derived to closely match clinical tests.

• Langille, Ellen; Al-Zahrani, Khalid N.; Ma, Zhibo; Liang, Minggao; Uuskula-Reimand, Liis & Espin, Roderic [Vis alle 36 forfattere av denne artikkelen] (2022). Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer. Cancer Discovery. ISSN 2159-8274. 12(12), s. 2930–2953. doi: 10.1158/2159-8290.CD-21-0865. Fulltekst i vitenarkiv
• Lilleborge, Marie; Falk, Ragnhild Sørum; Sørlie, Therese; Ursin, Giske & Hofvind, Solveig (2021). Can breast cancer be stopped? Modifiable risk factors of breast cancer among women with a prior benign or premalignant lesion. International Journal of Cancer. ISSN 0020-7136. 149(6), s. 1247–1256. doi: 10.1002/ijc.33680. Fulltekst i vitenarkiv Vis sammendrag

  Physical inactivity, high postmenopausal body mass index, alcohol consumption and use of menopausal hormone therapy are established risk factors for breast cancer. Less is known about whether these factors influence the risk of progression of benign and premalignant breast lesions to invasive breast cancer. This registry-based cohort study was based on women with a precancerous lesion who were followed for breast cancer. The cohort consisted of 11 270 women with a benign lesion, 972 women with hyperplasia with atypia and 2379 women with carcinoma in situ diagnosed and treated after participation in BreastScreen Norway, 2006-2016. Information on breast cancer risk factors was collected by a questionnaire administered with the invitation letter. Cox regression analysis was used to estimate the association between breast cancer and physical activity, body mass index, alcohol consumption, tobacco smoking and menopausal hormone therapy, adjusted for age. During follow-up, 274 women with a benign lesion, 34 women with hyperplasia with atypia and 118 women with carcinoma in situ were diagnosed with invasive breast cancer. We observed an increased risk of breast cancer associated with use of menopausal hormone therapy for women with a benign or premalignant lesion. Alcohol consumption and tobacco smoking showed suggestive increased risk of breast cancer among women with a benign lesion. We were only to a limited degree able to identify associations between modifiable risk factors of breast cancer and the disease among women with a precancerous lesion, and a larger study is needed to confirm or refute associations.

• Lien, Tonje Gulbrandsen; Ohnstad, Hege Oma; Lingjærde, Ole Christian; Vallon-Christersson, Johan; Aaserud, Marit & Sveli, My Anh Tu [Vis alle 12 forfattere av denne artikkelen] (2021). Sample preparation approach influences pam50 risk of recurrence score in early breast cancer. Cancers. 13(23). doi: 10.3390/cancers13236118. Fulltekst i vitenarkiv Vis sammendrag

  The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases.

• Xu, Haifeng; Lillebergen, Tonje Lien; Bergholtz, Helga; Fleischer, Thomas; Djerroudi, Lounes & Vincent-Salomon, Anne [Vis alle 8 forfattere av denne artikkelen] (2021). Multi-omics marker analysis enables early prediction of breast tumor progression. Frontiers in Genetics. 12, s. 1–14. doi: 10.3389/fgene.2021.670749. Fulltekst i vitenarkiv Vis sammendrag

  Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.

• Rye, Inga Hansine; Huse, Kanutte; Josefsson, Sarah Elisabet; Kildal, Wanja; Danielsen, Håvard Emil Greger & Schlichting, Ellen [Vis alle 28 forfattere av denne artikkelen] (2021). Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Molecular Oncology. ISSN 1574-7891. 16(1), s. 88–103. doi: 10.1002/1878-0261.13047. Fulltekst i vitenarkiv Vis sammendrag

  Sentinel lymph nodes are the first nodes draining the lymph from a breast and could reveal early changes in the host immune system upon dissemination of breast cancer cells. To investigate this, we performed single-cell immune profiling of lymph nodes with and without metastatic cells. Whereas no significant changes were observed for B-cell and natural killer (NK)-cell subsets, metastatic lymph nodes had a significantly increased frequency of CD8 T cells and a skewing toward an effector/memory phenotype of CD4 and CD8 T cells, suggesting an ongoing immune response. Additionally, metastatic lymph nodes had an increased frequency of TIGIT (T-cell immunoreceptor with Ig and ITIM domains)-positive T cells with suppressed TCR signaling compared with non-metastatic nodes, indicating exhaustion of effector T cells, and an increased frequency of regulatory T cells (Tregs) with an activated phenotype. T-cell alterations correlated with the percentage of metastatic tumor cells, reflecting the presence of metastatic tumor cells driving T effector cells toward exhaustion and promoting immunosuppression by recruitment or increased differentiation toward Tregs. These results show that immune suppression occurs already in early stages of tumor progression.

• Bergholtz, Helga; Carter, Jodi M.; Cesano, Alessandra; Cheang, Maggie Chon U.; Church, Sarah E. & Divakar, Prajan [Vis alle 32 forfattere av denne artikkelen] (2021). Best practices for spatial profiling for breast cancer research with the GeoMx® digital spatial profiler. Cancers. 13(17). doi: 10.3390/cancers13174456. Fulltekst i vitenarkiv
• Bergholtz, Helga; Kumar, Surendra; Wärnberg, Fredrik; Luders, Torben; Kristensen, Vessela N. & Sørlie, Therese (2020). Comparable cancer-relevant mutation profiles in synchronous ductal carcinoma in situ and invasive breast cancer. Cancer Reports. 3:e1248(3), s. 1–7. doi: 10.1002/cnr2.1248. Fulltekst i vitenarkiv Vis sammendrag

  Background Ductal carcinoma in situ (DCIS) comprises a diverse group of preinvasive lesions in the breast and poses a considerable clinical challenge due to lack of markers of progression. Genomic alterations are to a large extent similar in DCIS and invasive carcinomas, although differences in copy number aberrations, gene expression patterns, and mutations exist. In mixed tumors with synchronous invasive breast cancer (IBC) and DCIS, it is still unclear to what extent invasive tumor cells are directly derived from the DCIS cells. Aim Our aim was to compare cancer‐relevant mutation profiles of different cellular compartments in mixed DCIS/IBC and pure DCIS tumors. Methods and results We performed targeted sequencing of 50 oncogenes in microdissected tissue from three different epithelial cell compartments (in situ, invasive, and normal adjacent epithelium) from 26 mixed breast carcinomas. In total, 44 tissue samples (19 invasive, 16 in situ, 9 normal) were subjected to sequencing using the Ion Torrent platform and the AmpliSeq Cancer Hotspot Panel v2. For comparison, 10 additional, pure DCIS lesions were sequenced. Across all mixed samples, we detected 23 variants previously described in cancer. The most commonly affected genes were TP53, PIK3CA, and ERBB2. The PIK3CA:p.H1047R variant was found in nine samples from six patients. Most variants detected in invasive compartments were also found in the corresponding in situ cell compartment indicating a clonal relationship between the tumor stages. A lower frequency of variants were observed in pure DCIS lesions. Conclusion Similar mutation profiles between in situ and invasive cell compartments indicate a similar origin of the two tumor stages in mixed breast tumors. The lower number of potential driver variants found in pure DCIS compared with the in situ cell compartments of mixed tumors may imply that pure DCIS is captured earlier in the path of progression to invasive disease.

• Knutsen, Erik; Lellahi, Seyed Mohammad; Aure, Miriam Ragle; Nord, Silje; Fismen, Silje & Larsen, Kenneth Bowitz [Vis alle 14 forfattere av denne artikkelen] (2020). The expression of the long NEAT1_2 isoform is associated with human epidermal growth factor receptor 2-positive breast cancers. Scientific Reports. 10:1277, s. 1–14. doi: 10.1038/s41598-020-57759-4. Fulltekst i vitenarkiv Vis sammendrag

  The long non-coding RNA NEAT1 locus is transcribed into two overlapping isoforms, NEAT1_1 and NEAT1_2, of which the latter is essential for the assembly of nuclear paraspeckles. NEAT1 is abnormally expressed in a wide variety of human cancers. Emerging evidence suggests that the two isoforms have distinct functions in gene expression regulation, and recently it was shown that NEAT1_2, but not NEAT1_1, expression predicts poor clinical outcome in cancer. Here, we report that NEAT1_2 expression correlates with HER2-positive breast cancers and high-grade disease. We provide evidence that NEAT1_1 and NEAT1_2 have distinct expression pattern among different intrinsic breast cancer subtypes. Finally, we show that NEAT1_2 expression and paraspeckle formation increase upon lactation in humans, confirming what has previously been demonstrated in mice.

• Fougner, Christian; Bergholtz, Helga; Norum, Jens Henrik & Sørlie, Therese (2020). Re-definition of claudin-low as a breast cancer phenotype. Nature Communications. 11(1), s. 1–11. doi: 10.1038/s41467-020-15574-5. Fulltekst i vitenarkiv Vis sammendrag

  The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors are distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflect characteristics of their intrinsic subtype. Finally, we explore an alternative method for identifying claudin-low tumors and thereby uncover potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.

• Liu, Jingjing; Smissen, Wendy J. C. Prager van der; Collee, Margriet J.; Bolla, Manjeet K.; Wang, Qin & Kristensen, Vessela N. [Vis alle 82 forfattere av denne artikkelen] (2020). Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific Reports. 10:9688(1), s. 1–14. doi: 10.1038/s41598-020-65665-y. Fulltekst i vitenarkiv Vis sammendrag

  In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR=1.035, 95% CI=0.859–1.246, P=0.718 and OR=0.798, 95% CI=0.482–1.322, P=0.381 respectively), nor in specifc high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

• Engelsen, Agnete; Wnuk-Lipinska, Katarzyna; Bougnaud, Sébastien; Vatter, Fanny Pelissier; Tiron, Crina Elena & Villadsen, René [Vis alle 28 forfattere av denne artikkelen] (2020). AXL is a driver of stemness in normal mammary gland and breast cancer. iScience. 23(11), s. 1–40. doi: 10.1016/j.isci.2020.101649. Fulltekst i vitenarkiv Vis sammendrag

  The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.

• Bergholtz, Helga; Lien, Tonje Gulbrandsen; Swanson, David; Rattalma, Arnoldo Frigessi Di; Daidone, Maria Grazia & Tost, Jörg [Vis alle 8 forfattere av denne artikkelen] (2020). Contrasting DCIS and invasive breast cancer by subtype suggests basal-like DCIS as distinct lesions. NPJ breast cancer. 6. doi: 10.1038/s41523-020-0167-x. Fulltekst i vitenarkiv Vis sammendrag

  Ductal carcinoma in situ (DCIS) is a non-invasive type of breast cancer with highly variable potential of becoming invasive and affecting mortality. Currently, many patients with DCIS are overtreated due to the lack of specific biomarkers that distinguish low risk lesions from those with a higher risk of progression. In this study, we analyzed 57 pure DCIS and 313 invasive breast cancers (IBC) from different patients. Three levels of genomic data were obtained; gene expression, DNA methylation, and DNA copy number. We performed subtype stratified analyses and identified key differences between DCIS and IBC that suggest subtype specific progression. Prominent differences were found in tumors of the basal-like subtype: Basal-like DCIS were less proliferative and showed a higher degree of differentiation than basal-like IBC. Also, core basal tumors (characterized by high correlation to the basal-like centroid) were not identified amongst DCIS as opposed to IBC. At the copy number level, basal-like DCIS exhibited fewer copy number aberrations compared with basal-like IBC. An intriguing finding through analysis of the methylome was hypermethylation of multiple protocadherin genes in basal-like IBC compared with basal-like DCIS and normal tissue, possibly caused by long range epigenetic silencing. This points to silencing of cell adhesion-related genes specifically in IBC of the basal-like subtype. Our work confirms that subtype stratification is essential when studying progression from DCIS to IBC, and we provide evidence that basal-like DCIS show less aggressive characteristics and question the assumption that basal-like DCIS is a direct precursor of basal-like invasive breast cancer.

• Fougner, Christian; Bergholtz, Helga; Kuiper, Raoul; Norum, Jens Henrik & Sørlie, Therese (2019). Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers. Breast Cancer Research. ISSN 1465-5411. 21(1), s. 1–13. doi: 10.1186/s13058-019-1170-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors nor those of human claudin-low breast tumors have been thoroughly explored. Methods The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors. Results Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. Conclusions Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.

• Tekpli, Xavier; Lien, Tonje Gulbrandsen; Røssevold, Andreas Hagen; Nebdal, Daniel J.H.; Borgen, Elin & Ohnstad, Hege Oma [Vis alle 19 forfattere av denne artikkelen] (2019). An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nature Communications. 10:5499, s. 1–14. doi: 10.1038/s41467-019-13329-5. Fulltekst i vitenarkiv Vis sammendrag

  How mixtures of immune cells associate with cancer cell phenotype and affect pathogenesis is still unclear. In 15 breast cancer gene expression datasets, we invariably identify three clusters of patients with gradual levels of immune infiltration. The intermediate immune infiltration cluster (Cluster B) is associated with a worse prognosis independently of known clinicopathological features. Furthermore, immune clusters are associated with response to neoadjuvant chemotherapy. In silico dissection of the immune contexture of the clusters identified Cluster A as immune cold, Cluster C as immune hot while Cluster B has a pro-tumorigenic immune infiltration. Through phenotypical analysis, we find epithelial mesenchymal transition and proliferation associated with the immune clusters and mutually exclusive in breast cancers. Here, we describe immune clusters which improve the prognostic accuracy of immune contexture in breast cancer. Our discovery of a novel independent prognostic factor in breast cancer highlights a correlation between tumor phenotype and immune contexture.

• Bergholtz, Helga; Lien, Tonje Gulbrandsen; Ursin, Giske; Holmen, Marit Muri; Helland, Åslaug & Sørlie, Therese [Vis alle 7 forfattere av denne artikkelen] (2019). A Longitudinal Study of the Association between Mammographic Density and Gene Expression in Normal Breast Tissue. Journal of mammary gland biology and neoplasia. ISSN 1083-3021. 24(2), s. 163–175. doi: 10.1007/s10911-018-09423-x. Fulltekst i vitenarkiv Vis sammendrag

  High mammographic density (MD) is associated with a 4–6 times increase in breast cancer risk. For post-menopausal women,MD often decreases over time, but little is known about the underlying biological mechanisms. MD reflects breast tissuecomposition, and may be associated with microenvironment subtypes previously identified in tumor-adjacent normal tissue. Currently, these subtypes have not been explored in normal breast tissue. We obtained biopsies from breasts of healthy women at two different time points several years apart and performed microarray gene expression analysis. At time point 1, 65 samples with both MD and gene expression were available. At time point 2, gene expression and MD data were available from 17 women, of which 11 also had gene expression data available from the first time point. We validated findings from our previous study; negative correlation between RBL1 and MD in post-menopausal women, indicating involvement of the TGFβ pathway. We also found that breast tissue samples from women with a large decrease in MD sustained higher expression of genes in the histone family H4. In addition, we explored the previously defined active and inactive microenvironment subtypes and demonstrated that normal breast samples of the active subtype had characteristics similar to the claudin-low breast cancer subtype. Breast biopsies from healthy women are challenging to obtain, but despite a limited sample size, we have identified possible mechanisms relevant for changes in breast biology and MD over time that may be of importance for breast cancer risk and tumor initiation.

• Swanson, David; Lien, Tonje Gulbrandsen; Bergholtz, Helga; Sørlie, Therese & Rattalma, Arnoldo Frigessi Di (2019). A Bayesian two-way latent structure model for genomic data integration reveals few pan-genomic cluster subtypes in a breast cancer cohort. Bioinformatics. ISSN 1367-4803. 35(23), s. 4886–4897. doi: 10.1093/bioinformatics/btz381. Fulltekst i vitenarkiv Vis sammendrag

  Motivation Unsupervised clustering is important in disease subtyping, among having other genomic applications. As genomic data has become more multifaceted, how to cluster across data sources for more precise subtyping is an ever more important area of research. Many of the methods proposed so far, including iCluster and Cluster of Cluster Assignments (COCAs), make an unreasonable assumption of a common clustering across all data sources, and those that do not are fewer and tend to be computationally intensive. Results We propose a Bayesian parametric model for integrative, unsupervised clustering across data sources. In our two-way latent structure model, samples are clustered in relation to each specific data source, distinguishing it from methods like COCAs and iCluster, but cluster labels have across-dataset meaning, allowing cluster information to be shared between data sources. A common scaling across data sources is not required, and inference is obtained by a Gibbs Sampler, which we improve with a warm start strategy and modified density functions to robustify and speed convergence. Posterior interpretation allows for inference on common clusterings occurring among subsets of data sources. An interesting statistical formulation of the model results in sampling from closed-form posteriors despite incorporation of a complex latent structure. We fit the model with Gaussian and more general densities, which influences the degree of across-dataset cluster label sharing. Uniquely among integrative clustering models, our formulation makes no nestedness assumptions of samples across data sources so that a sample missing data from one genomic source can be clustered according to its existing data sources. We apply our model to a Norwegian breast cancer cohort of ductal carcinoma in situ and invasive tumors, comprised of somatic copy-number alteration, methylation and expression datasets. We find enrichment in the Her2 subtype and ductal carcinoma among those observations exhibiting greater cluster correspondence across expression and CNA data. In general, there are few pan-genomic clusterings, suggesting that models assuming a common clustering across genomic data sources might yield misleading results. Availability and implementation The model is implemented in an R package called twl (‘two-way latent’), available on CRAN. Data for analysis are available within the R package.

• Norum, Jens Henrik; Frings, Oliver; Kasper, Maria; Bergholtz, Helga; Thime, Helene Zell & Bergström, Åsa [Vis alle 11 forfattere av denne artikkelen] (2019). GLI1-induced mammary gland tumours are transplantable and maintain major molecular features. International Journal of Cancer. ISSN 0020-7136. doi: 10.1002/ijc.32522. Fulltekst i vitenarkiv
• Norum, Jens Henrik; Skarpen, Ellen; Brech, Andreas; Kuiper, Raoul; Waaler, Jo & Krauss, Stefan [Vis alle 7 forfattere av denne artikkelen] (2018). The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology. Biological Research (Print). ISSN 0716-9760. 51(1). doi: 10.1186/s40659-017-0151-6. Fulltekst i vitenarkiv Vis sammendrag

  Background: The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results: We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion: We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.

• Laurberg, Tinne; Tramm, Trine; Nielsen, Torsten; Alsner, Jan; Nord, Silje & Myhre, Simen [Vis alle 15 forfattere av denne artikkelen] (2018). Intrinsic subtypes and benefit from postmastectomy radiotherapy in node-positive premenopausal breast cancer patients who received adjuvant chemotherapy - results from two independent randomized trials. Acta Oncologica. ISSN 0284-186X. 57(1), s. 38–43. doi: 10.1080/0284186X.2017.1401735. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: The study of the intrinsic molecular subtypes of breast cancer has revealed differences among them in terms of prognosis and response to chemotherapy and endocrine therapy. However, the ability of intrinsic subtypes to predict benefit from adjuvant radiotherapy has only been examined in few studies. METHODS: Gene expression-based intrinsic subtyping was performed in 228 breast tumors collected from two independent post-mastectomy clinical trials (British Columbia and the Danish Breast Cancer Cooperative Group 82b trials), where pre-menopausal patients with node-positive disease were randomized to adjuvant radiotherapy or not. All patients received adjuvant chemotherapy and a subgroup of patients underwent ovarian ablation. Tumors were classified into intrinsic subtypes: Luminal A, Luminal B, HER2-enriched, Basal-like and Normal-like using the research-based PAM50 classifier. RESULTS: In the British Columbia study, patients treated with radiation had an overall significant lower incidence of locoregional recurrence compared to the controls. For Luminal A tumors the risk of loco-regional recurrence was low and was further lowered by adjuvant radiation. These findings were validated in the DBCG 82b study. The individual data from the two cohorts were merged, the hazard ratio (HR) for loco-regional recurrence associated with giving radiation was 0.34 (0.19 to 0.61) overall and 0.12 (0.03 to 0.52) for Luminal A tumors. CONCLUSIONS: In both postmastectomy trials, patients with Luminal A tumors turned out to have a significant lower incidence of loco-regional recurrence when randomized to adjuvant radiotherapy, leaving no indication to omit postmastectomy adjuvant radiation in pre-menopausal high-risk patients with Luminal A tumors. It was not possible to evaluate the effect of radiotherapy among the other subtypes because of limited sample sizes.

• Ohnstad, Hege Oma; Borgen, Elin; Falk, Ragnhild Sørum; Lien, Tonje Gulbrandsen; Aaserud, Marit & Sveli, My Anh Tu [Vis alle 14 forfattere av denne artikkelen] (2017). Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up. Breast Cancer Research. ISSN 1465-5411. 19(120). doi: 10.1186/s13058-017-0911-9. Fulltekst i vitenarkiv Vis sammendrag

  Background The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) pN0 patients not treated with chemotherapy. Methods Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995–1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). Results Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2− patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2− patients) yielded strong prognostic information. Among the HR+/HER2− pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2− pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2− population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). Conclusions The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

• Alcazar, Carlos Rodrigo Gil Del; Huh, Sung Jin; Ekram, Muhammad B.; Trinh, Anne; Liu, Lin L. & Beca, Francisco [Vis alle 30 forfattere av denne artikkelen] (2017). Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discovery. ISSN 2159-8274. 7(10), s. 1098–1115. doi: 10.1158/2159-8290.CD-17-0222. Fulltekst i vitenarkiv
• Lesurf, Robert; Aure, Miriam Ragle; Mørk, Hanne Håberg; Vitelli, Valeria; Lundgren, Steinar & Børresen-Dale, Anne-Lise [Vis alle 10 forfattere av denne artikkelen] (2016). Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer. Cell reports. 16(4), s. 1166–1179. doi: 10.1016/j.celrep.2016.06.051. Fulltekst i vitenarkiv Vis sammendrag

  Breast cancer consists of at least five main molecular “intrinsic” subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

• Sas-Chen, Aldema; Aure, Miriam Ragle; Leibovich, Limor; Carvalho, Silvia; Enuka, Yehoshua & Körner, Cindy [Vis alle 38 forfattere av denne artikkelen] (2016). LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer. EMBO Molecular Medicine. ISSN 1757-4676. 8(9), s. 1052–1064. doi: 10.15252/emmm.201606198. Fulltekst i vitenarkiv Vis sammendrag

  Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal‐like subtype associates with increased EGFR signaling, while another, the HER2‐enriched subtype, engages a kin of EGFR. Based on the premise that EGFR‐regulated lncRNAs might control the aggressiveness of basal‐like tumors, we identified multiple EGFR‐inducible lncRNAs in basal‐like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal‐like and in HER2‐positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo. In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.

• Skrbo, Nirma; Tenstad, Ellen; Mælandsmo, Gunhild; Sørlie, Therese & Andersen, Kristin (2015). From autonomy to community; new perspectives on tumorigenicity and therapy resistance. Cancer Treatment Reviews. ISSN 0305-7372. 41(10), s. 809–813. doi: 10.1016/j.ctrv.2015.10.004. Fulltekst i vitenarkiv
• Borgquist, Signe; Zhou, Wenjing; Jirström, Karin; Amini, Rose-Marie; Sollie, Thomas & Sørlie, Therese [Vis alle 9 forfattere av denne artikkelen] (2015). The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study. BMC Cancer. 15:468. doi: 10.1186/s12885-015-1479-3. Fulltekst i vitenarkiv
• Norum, Jens Henrik; Bergström, Åsa; Andersson, Agneta Birgitta; Kuiper, Raoul V.; Hoelzl, Maria A. & Sørlie, Therese [Vis alle 7 forfattere av denne artikkelen] (2015). A conditional transgenic mouse line for targeted expression of the stem cell marker LGR5. Developmental Biology. ISSN 0012-1606. 404(2), s. 35–48. doi: 10.1016/j.ydbio.2015.05.002. Fulltekst i vitenarkiv
• Potapenko, Ivan Olegovich; Luders, Torben; Russnes, Hege Elisabeth Giercksky; Helland, Åslaug; Sørlie, Therese & Kristensen, Vessela N. [Vis alle 10 forfattere av denne artikkelen] (2015). Glycan-related gene expression signatures in breast cancer subtypes; relation to survival. Molecular Oncology. ISSN 1574-7891. 9(4), s. 861–876. doi: 10.1016/j.molonc.2014.12.013. Fulltekst i vitenarkiv
• Tramm, Trine; Mohammed, Hayat; Myhre, Simen; Kyndi, Marianne; Alsner, Jan & Børresen-Dale, Anne-Lise [Vis alle 9 forfattere av denne artikkelen] (2014). Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort. Clinical Cancer Research. ISSN 1078-0432. 20(20), s. 5272–5280. doi: 10.1158/1078-0432.CCR-14-0458. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into “high LRR risk” and “low LRR risk” groups. PMRT significantly reduced risk of LRR in “high LRR risk” patients, whereas “low LRR risk” patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT

• Grinde, Maria Tunset; Skrbo, Nirma; Moestue, Siver Andreas; Rødland, Einar Andreas; Borgan, Eldrid & Kristian, Alexandr [Vis alle 14 forfattere av denne artikkelen] (2014). Interplay of choline metabolites and genes in patient-derived breast cancer xenografts. Breast Cancer Research. ISSN 1465-5411. 16(1). doi: 10.1186/bcr3597. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. In this study, the metabolomic and transcriptomic characteristics of a large panel of human breast cancer xenograft models were mapped, with focus on choline metabolism. Methods Tumor specimens from 34 patient-derived xenograft models were collected and divided in two. One part was examined using high-resolution magic angle spinning (HR-MAS) MR spectroscopy while another part was analyzed using gene expression microarrays. Expression data of genes encoding proteins in the choline metabolism pathway were analyzed and correlated to the levels of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC) using Pearson’s correlation analysis. For comparison purposes, metabolic and gene expression data were collected from human breast tumors belonging to corresponding molecular subgroups. Results Most of the xenograft models were classified as basal-like (N = 19) or luminal B (N = 7). These two subgroups showed significantly different choline metabolic and gene expression profiles. The luminal B xenografts were characterized by a high PCho/GPC ratio while the basal-like xenografts were characterized by highly variable PCho/GPC ratio. Also, Cho, PCho and GPC levels were correlated to expression of several genes encoding proteins in the choline metabolism pathway, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). These characteristics were similar to those found in human tumor samples. Conclusion The higher PCho/GPC ratio found in luminal B compared with most basal-like breast cancer xenograft models and human tissue samples do not correspond to results observed from in vitro studies. It is likely that microenvironmental factors play a role in the in vivo regulation of choline metabolism. Cho, PCho and GPC were correlated to different choline pathway-encoding genes in luminal B compared with basal-like xenografts, suggesting that regulation of choline metabolism may vary between different breast cancer subgroups. The concordance between the metabolic and gene expression profiles from xenograft models with breast cancer tissue samples from patients indicates that these xenografts are representative models of human breast cancer and represent relevant models to study tumor metabolism in vivo.

• Norum, Jan; Andersen, Kristin & Sørlie, Therese (2014). Lessons learned from the intrinsic subtypes of breast cancer in the quest for precision therapy. British Journal of Surgery. ISSN 0007-1323. 101(8), s. 925–938. doi: 10.1002/bjs.9562. Fulltekst i vitenarkiv
• Tramm, Trine; Kyndi, Marianne; Myhre, Simen; Nordgard, Silje H.; Alsner, Jan & Sørensen, Flemming Brandt [Vis alle 8 forfattere av denne artikkelen] (2014). Relationship between the prognostic and predictive value of the intrinsic subtypes and a validated gene profile predictive of loco-regional control and benefit from post-mastectomy radiotherapy in patients with high-risk breast cancer. Acta Oncologica. ISSN 0284-186X. 53(10), s. 1337–1346. doi: 10.3109/0284186X.2014.925580. Fulltekst i vitenarkiv
• Zhao, Xi; Rødland, Einar Andreas; Sørlie, Therese; Vollan, Hans Kristian Moen; Russnes, Hege Elisabeth Giercksky & Kristensen, Vessela N. [Vis alle 8 forfattere av denne artikkelen] (2014). Systematic assessment of prognostic gene signatures for breast cancer shows distinct influence of time and ER status. BMC Cancer. 14(211). doi: 10.1186/1471-2407-14-211. Fulltekst i vitenarkiv
• Skrbo, Nirma; Hjortland, Geir Olav; Kristian, Alexandr; Holm, Ruth; Nordgard, Silje H. & Prasmickaite, Lina [Vis alle 10 forfattere av denne artikkelen] (2014). Differential in vivo tumorigenicity of distinct subpopulations from a luminal-like breast cancer xenograft. PLOS ONE. 9(11). doi: 10.1371/journal.pone.0113278. Fulltekst i vitenarkiv Vis sammendrag

  Intratumor heterogeneity caused by genetic, phenotypic or functional differences between cancer cell subpopulations is a considerable clinical challenge. Understanding subpopulation dynamics is therefore central for both optimization of existing therapy and for development of new treatment. The aim of this study was to isolate subpopulations from a primary tumor and by comparing molecular characteristics of these subpopulations, find explanations to their differing tumorigenicity. Cell subpopulations from two patient derived in vivo models of primary breast cancer, ER+ and ER-, were identified. EpCAM+ cells from the ER+ model gave rise to tumors independently of stroma cell support. The tumorigenic fraction was further divided based on SSEA-4 and CD24 expression. Both markers were expressed in ER+ breast cancer biopsies. FAC-sorted cells based on EpCAM, SSEA-4 and CD24 expression were subsequently tested for differences in functionality by in vivo tumorigenicity assay. Three out of four subpopulations of cells were tumorigenic and showed variable ability to recapitulate the marker expression of the original tumor. Whole genome expression analysis of the sorted populations disclosed high similarity in the transcriptional profiles between the tumorigenic populations. Comparing the non-tumorigenic vs the tumorigenic populations, 44 transcripts were, however, significantly differentially expressed. A subset of these, 26 identified and named genes, highly expressed in the non-tumorigenic population, predicted longer overall survival (N = 737, p<0.0001) and distant metastasis free survival (DMFS) (N = 1379, p<0.0001) when performing Kaplan-Meier survival analysis using the GOBO online database. The 26 gene set correlated with longer DMFS in multiple breast cancer subgroups. Copy number profiling revealed no aberrations that could explain the observed differences in tumorigenicity. This study emphasizes the functional variability among cell populations that are otherwise genomically similar, and that the risk of breast cancer recurrence can only be eliminated if the tumorigenic abilities in multiple cancer cell subpopulations are inhibited.

• Myhre, Simen; Lingjærde, Ole Christian; Hennessy, Bryan T; Aure, Miriam Ragle; Carey, Mark S & Alsner, Jan [Vis alle 11 forfattere av denne artikkelen] (2013). Influence of DNA copy number and mRNA levels on the expression of breast cancer related proteins. Molecular Oncology. ISSN 1574-7891. 7(3), s. 704–718. doi: 10.1016/j.molonc.2013.02.018. Fulltekst i vitenarkiv
• Zhou, Wenjing; Jirström, Karin; Amini, Rose-Marie; Fjällskog, Marie Louise; Sollie, Thomas & Lindman, Henrik [Vis alle 9 forfattere av denne artikkelen] (2013). Molecular subtypes in ductal carcinoma in situ of the breast and their relation to prognosis: a population-based cohort study. BMC Cancer. 13:512. doi: 10.1186/1471-2407-13-512. Fulltekst i vitenarkiv
• Tramm, Trine; Hennig, Guido; Kyndi, Marianne; Alsner, Jan; Sørensen, Flemming & Myhre, Simen [Vis alle 8 forfattere av denne artikkelen] (2013). Reliable PCR quantitation of estrogen, progesterone and ERBB2 receptor mRNA from formalin-fixed, paraffin-embedded tissue is independent of prior macro-dissection. Virchows Archiv. ISSN 0945-6317. 463(6), s. 775–786. doi: 10.1007/s00428-013-1486-1. Fulltekst i vitenarkiv
• Borgan, Eldrid; Lindholm, Evita Maria; Moestue, Siver Andreas; Mælandsmo, Gunhild; Lingjærde, Ole Christian & Gribbestad, Ingrid S [Vis alle 9 forfattere av denne artikkelen] (2013). Subtype-specific response to bevacizumab is reflected in the metabolome and transcriptome of breast cancer xenografts. Molecular Oncology. ISSN 1574-7891. 7(1), s. 130–142. doi: 10.1016/j.molonc.2012.10.005. Fulltekst i vitenarkiv Vis sammendrag

  Antiangiogenic therapy with bevacizumab has shown varying results in breast cancer clinical trials. Identifying robust biomarkers for selecting patients who may benefit from such treatment and for monitoring response is important for the future use of bevacizumab. Two established xenograft models representing basal-like and luminal-like breast cancer were used to study bevacizumab treatment response on the metabolic and gene expression levels. Tumor samples were obtained from mice treated with bevacizumab, doxorubicin or a combination of the two drugs, and high resolution magic angle spinning magnetic resonance spectroscopy and gene expression microarray analysis was performed.

• Guiu, Séverine; Michiels, Stefan; Andre, Fabrice; Cortes, Javier; Denkert, Carsten & Leo, Angelo Di [Vis alle 14 forfattere av denne artikkelen] (2012). Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Annals of Oncology. ISSN 0923-7534. 23(12), s. 2997–3006. doi: 10.1093/annonc/mds586. Fulltekst i vitenarkiv
• Kristensen, Vessela N.; Vaske, Charles J.; Ursini-Siegel, Josie; Loo, Peter Van; Nordgard, Silje H. & Sachidanandam, Ravi [Vis alle 15 forfattere av denne artikkelen] (2012). Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 109(8), s. 2802–2807. doi: 10.1073/pnas.1108781108. Fulltekst i vitenarkiv
• Kim, Ji Young; Villadsen, René; Sørlie, Therese; Fogh, Louise; Gronlund, Signe Z & Fridriksdottir, Agla J. [Vis alle 15 forfattere av denne artikkelen] (2012). Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 109(16), s. 6124–6129. doi: 10.1073/pnas.1203203109. Fulltekst i vitenarkiv
• Akslen, Lars A.; Straume, Oddbjørn; Geisler, Stephanie; Sørlie, Therese; Chi, Jen-Tan Ashley & Aas, Turid [Vis alle 8 forfattere av denne artikkelen] (2011). Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer. British Journal of Cancer. ISSN 0007-0920. 105(1), s. 9–12. doi: 10.1038/bjc.2011.203. Fulltekst i vitenarkiv
• Sørlie, Therese (2011). How to personalise treatment in early breast cancer. European Journal of Cancer. ISSN 0959-8049. 47, s. S310–S311. doi: 10.1016/S0959-8049(11)70182-4. Fulltekst i vitenarkiv
• Borgan, Eldrid; Navon, Roy; Vollan, Hans Kristian Moen; Schlichting, Ellen; Sauer, Torill & Yakhini, Zohar [Vis alle 9 forfattere av denne artikkelen] (2011). Ischemia caused by time to freezing induces systematic microRNA and mRNA responses in cancer tissue. Molecular Oncology. ISSN 1574-7891. 5(6), s. 564–576. doi: 10.1016/j.molonc.2011.08.004. Fulltekst i vitenarkiv
• Zhao, Xi; Rødland, Einar Andreas; Sørlie, Therese; Naume, Bjørn; Langerød, Anita & Frigessi, Arnoldo [Vis alle 9 forfattere av denne artikkelen] (2011). Combining Gene Signatures Improves Prediction of Breast Cancer Survival. PLOS ONE. 6(3). doi: 10.1371/journal.pone.0017845. Fulltekst i vitenarkiv
• Russnes, Hege Elisabeth Giercksky; Vollan, Hans Kristian Moen; Lingjærde, Ole Christian; Krasnitz, Alexander; Lundin, Pär & Naume, Bjørn [Vis alle 23 forfattere av denne artikkelen] (2010). Genomic Architecture Characterizes Tumor Progression Paths and Fate in Breast Cancer Patients. Science Translational Medicine. ISSN 1946-6234. 2(38), s. 38–47. doi: 10.1126/scitranslmed.3000611. Fulltekst i vitenarkiv
• Potapenko, Ivan Olegovich; Haakensen, Vilde Drageset; Luders, Torben; Helland, Åslaug; Bukholm, Ida Rashida Khan & Sørlie, Therese [Vis alle 9 forfattere av denne artikkelen] (2010). Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Molecular Oncology. ISSN 1574-7891. 4(2), s. 98–118. doi: 10.1016/j.molonc.2009.12.001. Fulltekst i vitenarkiv
• Muggerud, Aslaug; Hallett, Michael; Johnsen, Hilde; Kleivi, Kristine; Zhou, Wenjing & Tahmasebpoor, Simin [Vis alle 11 forfattere av denne artikkelen] (2010). Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer. Molecular Oncology. ISSN 1574-7891. 4(4), s. 357–368. doi: 10.1016/j.molonc.2010.06.007. Fulltekst i vitenarkiv
• Borgan, Eldrid; Sitter, Beathe; Lingjærde, Ole Christian; Johnsen, Hilde; Lundgren, Steinar & Bathen, Tone Frost [Vis alle 9 forfattere av denne artikkelen] (2010). Merging transcriptomics and metabolomics - advances in breast cancer profiling. BMC Cancer. 10. doi: 10.1186/1471-2407-10-628. Fulltekst i vitenarkiv Vis sammendrag

  Background Combining gene expression microarrays and high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) of the same tissue samples enables comparison of the transcriptional and metabolic profiles of breast cancer. The aim of this study was to explore the potential of combining these two different types of information. Methods Breast cancer tissue from 46 patients was analyzed by HR MAS MRS followed by gene expression microarrays. Two strategies were used to combine the gene expression and metabolic data; first using multivariate analyses to identify different groups based on gene expression and metabolic data; second correlating levels of specific metabolites to transcripts to suggest new hypotheses of connections between metabolite levels and the underlying biological processes. A parallel study was designed to address experimental issues of combining microarrays and HR MAS MRS. Results In the first strategy, using the microarray data and previously reported molecular classification methods, the majority of samples were classified as luminal A. Three subgroups of luminal A tumors were identified based on hierarchical clustering of the HR MAS MR spectra. The samples in one of the subgroups, designated A2, showed significantly lower glucose and higher alanine levels than the other luminal A samples, suggesting a higher glycolytic activity in these tumors. This group was also enriched for genes annotated with Gene Ontology (GO) terms related to cell cycle and DNA repair. In the second strategy, the correlations between concentrations of myo-inositol, glycine, taurine, glycerophosphocholine, phosphocholine, choline and creatine and all transcripts in the filtered microarray data were investigated. GO-terms related to the extracellular matrix were enriched among the genes that correlated the most to myo-inositol and taurine, while cell cycle related GO-terms were enriched for the genes that correlated the most to choline. Additionally, a subset of transcripts was identified to have slightly altered expression after HR MAS MRS and was therefore removed from all other analyses. Conclusions Combining transcriptional and metabolic data from the same breast carcinoma sample is feasible and may contribute to a more refined subclassification of breast cancers as well as reveal relations between metabolic and transcriptional levels. See Commentary: http://www.biomedcentral.com/1741-7015/8/73

• Muggerud, Aslaug; Rønneberg, Jo Anders; Wärnberg, Fredrik; Botling, Johan; Busato, Florence & Jovanovic, Jovana [Vis alle 12 forfattere av denne artikkelen] (2010). Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Research. ISSN 1465-5411. 12(1). doi: 10.1186/bcr2466. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. Methods Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16 INK4a , ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. Results Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. Conclusions Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.

• Myhre, Simen; Mohammed, Hayat; Tramm, Trine; Alsner, Jan; Finak, Greg & Park, Morag [Vis alle 10 forfattere av denne artikkelen] (2010). In Silico Ascription of Gene Expression Differences to Tumor and Stromal Cells in a Model to Study Impact on Breast Cancer Outcome. PLOS ONE. 5(11). doi: 10.1371/journal.pone.0014002. Fulltekst i vitenarkiv
• Podo, F; Buydens, LMC; Degani, H; Hilhorst, Riet; Klipp, Edda & Gribbestad, Ingrid S [Vis alle 18 forfattere av denne artikkelen] (2010). Triple-negative breast cancer: Present challenges and new perspectives. Molecular Oncology. ISSN 1574-7891. 4(3), s. 209–229. doi: 10.1016/j.molonc.2010.04.006. Fulltekst i vitenarkiv
• Muggerud, Aslaug Aamodt; Edgren, H; Wolf, M; Kleivi, Kristine; Dejeux, E & Tost, J [Vis alle 8 forfattere av denne artikkelen] (2009). Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8A in a breast cancer cell line. BMC Medical Genomics. 2. doi: 10.1186/1755-8794-2-26. Fulltekst i vitenarkiv
• Zhou, WJ; Muggerud, Aslaug Aamodt; Vu, Phuong Ngoc Thi; Due, Eldri Undlien; Sørlie, Therese & Børresen-Dale, Anne-Lise [Vis alle 8 forfattere av denne artikkelen] (2009). Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution. Molecular Oncology. ISSN 1574-7891. 3(3), s. 214–219. doi: 10.1016/j.molonc.2009.03.001. Fulltekst i vitenarkiv
• Agarwal, R; Gonzalez-Angulo, AM; Myhre, Simen; Carey, M; Lee, JS & Overgaard, Jens [Vis alle 19 forfattere av denne artikkelen] (2009). Integrative Analysis of Cyclin Protein Levels Identifies Cyclin B1 as a Classifier and Predictor of Outcomes in Breast Cancer. Clinical Cancer Research. ISSN 1078-0432. 15(11), s. 3654–3662. doi: 10.1158/1078-0432.CCR-08-3293. Fulltekst i vitenarkiv
• Bergamaschi, Anna; Hjortland, Geir Olav; Triulzi, T; Sørlie, Therese; Johnsen, Hilde & Ree, Anne Hansen [Vis alle 12 forfattere av denne artikkelen] (2009). Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models. Molecular Oncology. ISSN 1574-7891. 3(5-6), s. 469–482. doi: 10.1016/j.molonc.2009.07.003. Fulltekst i vitenarkiv
• Bergamaschi, Anna; Tagliabue, Elda; Sørlie, Therese; Naume, Bjørn; Triulzi, Tiziana & Orlandi, Rosario [Vis alle 13 forfattere av denne artikkelen] (2008). Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. Journal of Pathology. ISSN 0022-3417. 214(3), s. 357–367. doi: 10.1002/path.2278. Fulltekst i vitenarkiv
• Nordgard, Silje H.; Nordgard, Silje H.; Alnæs, Grethe I.G.; Alnaes, GIG; Hihn, Björn & Lingjærde, Ole Chr. [Vis alle 13 forfattere av denne artikkelen] (2008). Pathway based analysis of SNPs with relevance to 5-FU therapy: Relation to intratumoral mRNA expression and survival. International Journal of Cancer. ISSN 0020-7136. 123(3), s. 577–585. doi: 10.1002/ijc.23541. Fulltekst i vitenarkiv
• Naume, Bjørn; Zhao, Xi; Synnestvedt, Marit; Borgen, Elin; Giercksky, Hege E & Lingjærde, Ole Christian [Vis alle 13 forfattere av denne artikkelen] (2007). Presence of bone marrow micrometastasis is associated with different recurrence risk within molecular subtypes of breast cancer. Molecular Oncology. ISSN 1574-7891. 1(2), s. 160–171. doi: 10.1016/j.molonc.2007.03.004. Fulltekst i vitenarkiv Vis sammendrag

  Expression profiles of primary breast tumors were investigated in relation to disseminated tumor cells (DTCs) in bone marrow (BM) in order to increase our understanding of the dissemination process. Tumors were classified into five pre-defined molecular subtypes, and presence of DTC identified (at median 85 months follow-up) a subgroup of luminal A patients with particular poor outcome (p = 0.008). This was not apparent for other tumor subtypes. Gene expression profiles associated with DTC and with systemic relapse for luminal A patients were identified. This study suggests that DTC in BM differentially distinguishes clinical outcome in patients with luminal A type tumors and that DTC-associated gene expression analysis may identify genes of potential importance in tumor dissemination.

• Sørlie, Therese; Perou, Charles M.; Fan, Cheng; Geisler, Stephanie; Aas, Turid & Nobel, Andrew [Vis alle 11 forfattere av denne artikkelen] (2006). Gene expression profiles do not consistently predict the clinical treatment response in locally advanced breast cancer. Molecular Cancer Therapeutics. ISSN 1535-7163. 5(11), s. 2914–2918. doi: 10.1158/1535-7163.MCT-06-0126. Fulltekst i vitenarkiv
• Muggerud, Aslaug Aamodt; Johnsen, Hilde; Barnes, Debra A.; Steel, Adam; Lønning, Per Eystein & Lonning, PE [Vis alle 9 forfattere av denne artikkelen] (2006). Evaluation of MetriGenix custom 4D (TM) arrays applied for detection of breast cancer subtypes. BMC Cancer. 6. doi: 10.1186/1471-2407-6-59. Fulltekst i vitenarkiv Vis sammendrag

  Background Previously, a total of five breast cancer subtypes have been identified based on variation in gene expression patterns. These expression profiles were also shown to be associated with different prognostic value. In this study tumour samples from 27 breast cancer patients, previously subtyped by expression analysis using DNA microarrays, and four controls from normal breast tissue were included. A new MetriGenix 4D™ array proposed for diagnostic use was evaluated. Methods We applied MetriGenix custom 4D™ arrays for the detection of previously defined molecular subtypes of breast cancer. MetriGenix 4D™ arrays have special features including probe immobilization in microchannels with chemiluminescence detection that enable shorter hybridization time. Results The MetriGenix 4D™ array platform was evaluated with respect to both the accuracy in classifying the samples as well as the performance of the system itself. In a cross validation analysis using "Nearest Shrunken Centroid classifier" and the PAM software, 77% of the samples were classified correctly according to earlier classification results. Conclusion The system shows potential for fast screening; however, improvements are needed.

• Kristensen, Vessela N.; Edvardsen, Hege; Tsalenko, Anya; Nordgard, Silje H.; Sørlie, Therese & Sharan, Roded [Vis alle 14 forfattere av denne artikkelen] (2006). Genetic variation in putative regulatory loci controlling gene expression in breast cancer. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 103(20), s. 7735–7740. Fulltekst i vitenarkiv Vis sammendrag

  Candidate single-nucleotide polymorphisms (SNPs) were analyzed for associations to an unselected whole genome pool of tumor mRNA transcripts in 50 unrelated patients with breast cancer. SNPs were selected from 203 candidate genes of the reactive oxygen species pathway. We describe a general statistical framework for the simultaneous analysis of gene expression data and SNP genotype data measured for the same cohort, which revealed significant associations between subsets of SNPs and transcripts, shedding light on the underlying biology. We identified SNPs in EGF, IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts, indicating the presence of regulatory SNPs in these genes. SNPs were found to act in trans in a total of 115 genes. SNPs in 43 of these 115 genes were found to act both in cis and in trans. Finally, subsets of SNPs that share significantly many common associations with a set of transcripts (biclusters) were identified. The subsets of transcripts that are significantly associated with the same set of SNPs or to a single SNP were shown to be functionally coherent in Gene Ontology and pathway analyses and coexpressed in other independent data sets, suggesting that many of the observed associations are within the same functional pathways. To our knowledge, this article is the first study to correlate SNP genotype data in the germ line with somatic gene expression data in breast tumors. It provides the statistical framework for further genotype expression correlation studies in cancer data sets.

• Kristensen, Vessela Nedelcheva; Sorlie, Therese; Sørlie, Therese; Geisler, Jürgen; Geisler, E & Yoshimura, Noriko [Vis alle 14 forfattere av denne artikkelen] (2005). Effects of anastrozole on the intratumoral gene expression in locally advanced breast cancer. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 95(1-5), s. 105–111. doi: 10.1016/j.jsbmb.2005.04.028. Fulltekst i vitenarkiv
• Kristensen, Vessela N.; Sørlie, Therese; Geisler, Jurgen; Langerød, Anita; Yoshimura, Noriko & Kåresen, Rolf [Vis alle 9 forfattere av denne artikkelen] (2005). Gene expression profiling of breast cancer in relation to estrogen receptor status and estrogen-metabolizing enzymes: Clinical implication. Clinical Cancer Research. ISSN 1078-0432. 11, s. 878s–883s. Fulltekst i vitenarkiv
• Sørlie, Therese; Johnsen, Hilde; Vu, Phuong Ngoc Thi; Lind, Gruo Elisabeth; Lothe, Ragnhild A & Børresen-Dale, Anne-Lise (2005). Mutation screening of the TP53 gene by temporal temperature gel electrophoresis (TTGE). Methods in molecular biology. ISSN 1064-3745. 291, s. 207–216. Fulltekst i vitenarkiv

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• Lønning, Per Eystein; Sørlie, Therese & Børresen-Dale, Anne-Lise (2005). Genomics in breast cancer - therapeutic implications. Nature Publishing Group. 8 s. Fulltekst i vitenarkiv

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• Pradhan, Manohar; Kildal, Wanja; Kleppe, Andreas; Tobin, Kari Anne Risan; Nikolaysen, Filip & Mascialino, Barbara [Vis alle 12 forfattere av denne artikkelen] (2025). Prognostic Value Of Different Stages Of Maturation Of Tertiary Lymphoid Structures In Molecular Subgroups Of Endometrial Carcinoma. International Journal of Gynecological Cancer. ISSN 1048-891X. 35(2), s. 100104–100104. doi: 10.1016/j.ijgc.2024.100104. Fulltekst i vitenarkiv Vis sammendrag

  Introduction/Background Tertiary lymphoid structures (TLSs) are organized clusters of lymphoid cells at various maturation stages with potential prognostic and predictive impact for response to immunotherapy in several cancer types. We assessed the prognostic significance of TLSs in patients with molecularly classified endometrial carcinoma (EC). Methodology This retrospective cohort included 1221 patients with molecularly classified EC treated at Oslo University Hospital 2006-2017. Formalin-fixed, paraffin-embedded tissue sections from hysterectomy specimens were immunohistochemically stained for CD21, Ki-67, CD3 and CD20. TLSs were categorized as mature (CD21+/Ki-67+), immature (CD21+/Ki-67–), lymphoid aggregates (CD21–, CD3+, and CD20+), or negative (CD21–/no CD3/CD20+ clusters). Univariable and multivariable analyses were performed to assess the association between TLS stages and time to recurrence (TTR). Results We identified 517 patients with lymphoid aggregates, 224 with immature TLSs, 138 with mature TLSs, and 342 TLS-negative cases. TLSs were more frequent in POLE-mutated (98%, 94/96) and MMRd (MMR deficient) tumours (87%, 321/368) compared to p53 abnormal (63%, 175/275) and no specific molecular profile (60%, 278/462) tumours (p<0.001). TLS presence of any maturity was significantly associated with longer TTR in univariable (p<0.001) and multivariable analysis (p<0.001). Compared to TLS-negative cases, the hazard ratio was 0.69 (95% confidence interval (95%CI): 0.54-0.89) for lymphoid aggregates, 0.45 (95%CI: 0.31-0.64) for immature TLSs, and 0.27 (95%CI: 0.16-0.44) for mature TLSs in multivariable analyses. In stratified analysis by molecular subgroup, presence of all maturity stages of TLSs remained significantly associated with longer TTR in patients in MMRd and NSMP tumours in multivariable analysis. TLSs is a favourable prognostic marker for EC patients, especially in the MMRd and NSMP subgroups. Conclusion TLSs were predominantly found in patients with POLE-mutated and MMRd tumours. Prognosis improved progressively with TLS maturation stage, with longest TTR in patients with mature TLSs. Evaluating TLSs may provide additional prognostic information across molecular subgroups. Disclosures This supported collaborative study was funded by GSK (OSF.IO/JHEVG” title="https://doi.org/10.17605/OSF.IO/JHEVG">https://doi.org/10.17605/OSF.IO/JHEVG). BM, DS, and HE are full-time employees of GSK and hold stock and/or stock options. HE holds stock/stock options i Abbvie. KL reports the following conflicts of interest outside the submitted work: Participation on data safety monitoring or advisory boards of Eisai, MSD, Nykode, AstraZeneca, GSK and Karyopharm (honoraria paid to institution); speaker fee from MSD; GSK and Astra Zeneca and research funding paid to institution from GSK. All remaining authors have declared no conflicts of interest.

• Skrbo, Nirma; Kirik, U.; Kristian, Alexandr; Cifani, P.; Antberg, L. & Moestue, Siver Andreas [Vis alle 11 forfattere av denne artikkelen] (2016). Protein expression analysis of intratumor heterogeneity in a luminal-like breast cancer xenograft. Fulltekst i vitenarkiv
• Moestue, Siver Andreas; Grinde, Maria Tunset; Marangoni, Eilsabetta; Sørlie, Therese; Engebråten, Olav & Mælandsmo, Gunhild [Vis alle 8 forfattere av denne artikkelen] (2013). Cytosolic phospholipase A2 (cPLA2) as a therapeutic target in basal-like breast cancer. Fulltekst i vitenarkiv
• Moestue, Siver Andreas; Grinde, Maria Tunset; Marangoni, Elisabetta; Skrbo, Nirma; Rødland, Einar Andreas & Borgan, Eldrid [Vis alle 15 forfattere av denne artikkelen] (2013). Interplay of choline metabolites and genes in patient-derived breast cancer xenografts. Fulltekst i vitenarkiv
• Borgan, Eldrid; Sitter, Beathe; Lingjærde, Ole Christian; Johnsen, Hilde; Lundgren, Steinar & Bathen, Tone Frost [Vis alle 9 forfattere av denne artikkelen] (2010). Transcriptomics meets metabolomics - correlating snapshots of breast cancer metabolism. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 140–140. Fulltekst i vitenarkiv
• Børresen-Dale, Anne-Lise; Sørlie, Therese & Kristensen, Vessela N. (2010). On the molecular biology of breast cancer Preface. Molecular Oncology. ISSN 1574-7891. 4(3), s. 171–173. doi: 10.1016/j.molonc.2010.04.007. Fulltekst i vitenarkiv
• Sørlie, Therese; Borgan, Eldrid; Myhre, Simen; Vollan, Hans Kristian Moen; Russnes, Hege Elisabeth Giercksky & Zhao, Xi [Vis alle 9 forfattere av denne artikkelen] (2010). The importance of gene-centring microarray data. The Lancet Oncology. ISSN 1470-2045. 11(8), s. 719–720. Fulltekst i vitenarkiv
• Potapenko, Ivan Olegovich; Haakensen, Vilde Drageset; Luders, Torben; Helland, Åslaug; Bukholm, Ida Rashida Khan & Sørlie, Therese [Vis alle 9 forfattere av denne artikkelen] (2010). Glycan gene expression signatures distinguish normal and malignant breast tissue; possible role in diagnosis and progression. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 102–102. Fulltekst i vitenarkiv
• Sørlie, Therese; Muggerud, Aslaug; Hallett, Michael; Johnsen, Hilde; Sahlberg, Kristine Kleivi & Botling, Johan [Vis alle 8 forfattere av denne artikkelen] (2010). Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 200–201. Fulltekst i vitenarkiv
• Potapenko, Ivan Olegovich; Haakensen, Vilde Drageset; Myhre, Simen; Luder, T; Naume, Bjørn & Lingjærde, Ole Christian [Vis alle 10 forfattere av denne artikkelen] (2009). Glycan signatures of breast cancer; possible role in diagnosis and progression of the disease. Annals of Oncology. ISSN 0923-7534. 20, s. 49–49. Fulltekst i vitenarkiv
• Sørlie, Therese (2009). Introducing Molecular Subtyping of Breast Cancer Into the Clinic? Journal of Clinical Oncology. ISSN 0732-183X. 27(8), s. 1153–1154. doi: 10.1200/JCO.2008.20.6276. Fulltekst i vitenarkiv
• Muggerud, Aslaug Aamodt; Sørlie, Therese; Kleivi, Kristine & Børresen-Dale, Anne-Lise (2009). Genetic and epigenetic alterations in breast tumour progression: The transition from in situ to invasive cancer. Universitetet i Oslo. ISSN 9788280723369. Fulltekst i vitenarkiv

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