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oai:www.repository.cam.ac.uk:1810/3817602025-12-19T22:08:09Zcom_1810_245118com_1810_34581col_1810_245119

The impact of ARID1A loss on ER+ breast cancer: mechanistic insights and therapeutic opportunities https://doi.org/10.17863/CAM.116832 Borsari, Giacomo Carroll, jason Metastasis is the leading cause of mortality in breast cancer patients. Up to 12 % of all ER+ breast cancer metastases harbour mutations in ARID1A, a critical subunit of the SWI/SNF chromatin remodelling complex. In 2020, Nagarajan et al. have shown that ARID1A mutations contribute to resistance to endocrine therapy in breast tumours while simultaneously increasing their sensitivity to epigenetic BET inhibitors. This project aims to explore the role of ARID1A loss in driving metastatic ER+ breast cancer, using the most clinically relevant mouse intraductal xenografting model. In vivo investigations demonstrated that the loss of ARID1A leads to increased tumour aggressiveness and elevated metastatic potential. Functionally, ARID1A loss induced significant chromatin structure remodelling and reprogrammed transcriptional profiles. Unbiased proteomic analysis revealed that ARID1A-depleted tumours exhibit a reduced reliance on the pioneer factor FOXA1, as evidenced by a marked collapse of the FOXA1 interactome. Conversely, these tumours transitioned to a BRD3-driven state, which was recruited to newly accessible genomic regions. This recruitment promoted transcription elongation by mediating the phosphorylation of Ser2 on the RNA polymerase II C-terminal domain. Using a cutting-edge PROTAC approach targeting BRD2, BRD3, and BRD4, in vivo studies showed impaired growth of ARID1A-depleted tumours and a reduction in metastatic burden. Further investigations in other tumour types supported these findings, suggesting a pan-cancer ’override’ mechanism triggered by ARID1A loss. Overall, this project provides a comprehensive understanding of the molecular and functional consequences associated with ARID1A loss in breast cancer. The findings support the hypothesis that ARID1A-depleted cancers exhibit hypersensitivity to BET proteins- targeting approaches, opening potential therapeutic avenues for targeted treatment. University of Cambridge 2024-09-26 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/381760 https://www.repository.cam.ac.uk/bitstreams/08d7ea4c-f6ee-4813-aff0-f4a6b36a4e55/download 4c4fda5ea27d231a332adac01e61006b https://www.repository.cam.ac.uk/bitstreams/02ee37ae-bc55-4dfd-bf0b-b482999ddd31/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved ER+ breast cancer ARID1A BET proteins Omics