ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response

Using genome-wide CRISPR screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the most critical factors required for response to two classes of Estrogen Receptor-alpha (ER) antagonists as these SWI/SNF-specific gene knockouts lead to drug resistance. Unexpectedly, ARID1A was also the top candidate for response to the BET inhibitor JQ1, but in the opposite direction, where loss of ARID1A sensitised breast cancer cells to BET inhibition. We show that ARID1A is a repressor which binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but FOXA1-dependent and active ER-independent manner. Deletion of ARID1A resulted in loss of Histone Deacetylase 1 (HDAC1) binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease and our findings provide mechanistic insight into this process whilst revealing rational treatment strategies for these patients.