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Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Group Leader Tiziana Bonaldi, European Institute of Oncology, Italy
- Second opponent: Professor Sushma Nagaraja Grellscheid, University of Bergen (UiB)
- Third member and chair of the evaluation committee: Associate professor Coen Campsteijn, University of Oslo
Chair of the Defence
Professor Manuela Zucknick, University of Oslo
Principal Supervisor
Researcher, Project Leader Thomas Fleischer, Oslo University Hospital (OUS)
Summary
Alterations in DNA methylation occurs early during cancer development and plays a critical role in regulating gene expression. However, the precise regulatory role and clinical implications of these alterations are still poorly understood. This thesis aims to advance our understanding of the functional effects of epigenetic alterations on the transcriptome in breast cancer and across cancer types, and to identify novel epigenetic alterations contributing to the carcinogenesis that may represent future targets for epigenetic therapy with the intent of impeding tumor growth and progression.
Through the work of this thesis, we identify and characterize genome-wide alterations in DNA methylation linked to abnormal gene expression levels in breast cancer and across cancer types. We find that loss of enhancer methylation plays a key role in regulating cancer progression and is linked with transcription factor binding and concomitant upregulation of genes related to proliferation, hormone-signaling and metabolism. By using a CRISPR system based on the dead Cas9 protein fused with DNA methyltransferase 3A, we show that targeted DNA methylation at the hypomethylated AGR2 and PGR enhancers in breast cancer can normalize the expression levels of these genes towards a pre-cancerous level.
Our findings highlight the potential of targeted DNA methylation as a potential clinical tool in cancer treatment in the future, either alone or as a supplement to conventional treatment to improve treatment response and survival.
Additional information
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