BRD3 mediates transcriptional reprogramming in ARID1A-deficient ER+ breast cancer

ABSTRACT: Metastasis is the major cause of breast cancer-related deaths. ARID1A mutations occur in up to 12% of ER+ breast cancer metastasis, resulting in resistance to endocrine therapy, but an unexpected gain in sensitivity to BET inhibitors. Using the mouse intraductal xenografting model we showed that the loss of ARID1A leads to aggressive tumours with elevated metastatic potential and significant changes in chromatin structure and transcriptional profiles. ARID1A-depleted tumours rely less on FOXA1/ER and more on BRD proteins, particularly BRD3. Using a PROTAC targeting BET proteins, we can inhibit ARID1A-depleted tumours and reduce metastatic burden. However, we reveal important limitations with BET inhibitors, as revealed in numerous failed clinical trials. Analysis of other tumour types corroborated the consequences of ARID1A loss observed in breast cancer models, suggesting a pan-cancer ‘over-ride’ mechanism. Collectively, our findings suggest that ARID1A-depleted cancers gain hyper-sensitivity to bromodomain proteins, while also revealing opportunities and limitations with their inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Breast Cancer

SUBMITTER: Valar Nila Roamio Franklin  

LAB HEAD: Clive D'Santos

PROVIDER: PXD051554 | Pride | 2026-10-08

REPOSITORIES: Pride