Abstract 949: ARID1A is a critical regulator of luminal identity and therapeutic response in estrogen receptor-positive breast cancer

Abstract

Abstract Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common somatic alteration of the SWI/SNF complex across all cancers including estrogen receptor positive (ER)+ breast cancer. We have recently reported that ARID1A inactivating mutations are present at a high frequency in advanced endocrine resistant ER+ breast cancer. However, the mechanisms whereby disruption of ARID1A influences breast cancer progression and/or endocrine therapy resistance are unknown. In order to elucidate mechanisms of resistance to endocrine therapy, we performed an epigenome CRISPR/CAS9 knockout screen that identified ARID1A as the top candidate whose loss determines resistance to the ER degrader, fulvestrant. ARID1A knockout cells were found to be less responsive to endocrine therapy compared to intact ARID1A cells in vitro and in vivo. These observations led us to undertake a comprehensive chromatin-based mechanistic characterization of ARID1A loss in ER+ breast cancer and its role in endocrine therapy response. ARID1A disruption in ER+ breast cancer cells led to widespread changes in chromatin accessibility converging on the master transcription factors (TFs) that regulate gene expression programs critical for luminal (ER+) lineage identity. Global transcriptome profiling of ARID1A knockout cell lines and patient samples harboring ARID1A inactivating mutations revealed an enrichment for basal-like (ER-) gene expression signatures. The state of increased cellular plasticity of luminal cells that acquire a basal-like phenotype upon ARID1A inactivation is enabled by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the major luminal-lineage determining transcription factors including ER, FOXA1, and GATA3. Thus, through widespread chromatin reprograming and functional regulation of mater luminal TFs, tumor cells alter lineage fidelity and become less responsive to luminal-specific anti-ER therapy. We also show that ARID1A regulates genome-wide ER-chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in the determination of breast luminal cell identity and endocrine therapeutic response in breast cancer. Citation Format: Eneda Toska, Guotai Xu, Sagar Chhangawala, Emiliano Cocco, Pedram Razavi, Jordan Otto, Yanyan Cai, Carmen Chan, Drew R. D' Avino, Clayton Collings, Ross L. Levine, Maurizo Scaltriti, Jorge S. Reis-Filho, Cigall Kadoch, Christina Leslie, Jose Baselga. ARID1A is a critical regulator of luminal identity and therapeutic response in estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 949.