Abstract 5290: Investigating the intrinsic epigenetic dependencies of estrogen receptor positive and ESR1 mutant breast cancer

Abstract Background: Estrogen receptor alpha (ERα) is a nuclear steroid hormone receptor that regulates transcription through DNA binding. ER is a lineage defining transcription factor (TF) that drives approximately 70% of breast cancer (BC) cases expressing the receptor. Aromatase inhibitor or selective estrogen receptor modulator treatment are first-line endocrine therapies for the treatment of ER+ BC, and they function by disrupting ligand availability or antagonizing ER, respectively. Activating mutations in ESR1, the gene encoding ERα, are enriched in approximately 25% of metastatic cases. ESR1 mutations lock ER in an active conformation, conferring ligand-independent signaling, endocrine therapy resistance, and increased proliferative capacity. Both wild-type and mutant ER primarily act through enhancer elements rather than promoters, relying on a network of transcriptional co-factors and chromatin remodeling complexes to facilitate enhancer accessibility. Targeting these epigenetic dependencies represents a promising therapeutic strategy. The mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex interacts with ER-associated transcription factors, including FOXA1, and supports enhancer activity and ER recruitment. Thus, disrupting mSWI/SNF function may impair ER-driven transcriptional programs in ER+ BC. Methods: mSWI/SNF activity was perturbed using either a dual PROTAC degrader of SMARCA2/4 or a selective SMARCA2/4 ATPase inhibitor. Pharmacological effect was assessed in a variety of preclinical models of ER+ and ESR1 mutant BC including cell lines and patient-derived xenografts (PDX). Mechanisms of action of ER signaling disruption and mSWI/SNF dependence were investigated using multi-omics techniques such as RNA-seq, ATAC-seq, ChIP-seq, and RIME. Results: We showed that ER+ BC cell lines are preferentially sensitive to mSWI/SNF complex inactivation at nanomolar concentrations of both compounds. We also demonstrated significant anti-tumor activity in both ER wild type and mutant PDX models. This anti-proliferative phenotype is shown to be driven by ER signaling axis disruption, with key downstream targets like c-Myc and CCND1 being downregulated. Mechanistically, we demonstrate these effects are mediated by reduced chromatin accessibility at enhancer regions, changes in the FOXA1 and ER cistromes, and a disruption of the ER interactome. Conclusions: We establish the mSWI/SNF complex as a critical epigenetic dependency that sustains ER transcriptional activity in ER+ BC. Therapeutic targeting of SMARCA2/4 effectively disrupts enhancer function, impairs ER signaling, and suppresses tumor growth. mSWI/SNF-directed therapies therefore represent a promising strategy for advanced and endocrine-resistant ER+ breast cancers. Citation Format: Andrej Coleski, Eleanor Young, Sumit Das, Xuhong Cao, Shannon VanAken, Fengyun Su, Yizhi Cao, Rui Wang, James M. Rae, Abhijit Parolia, Yuanyuan Qiao, Lanbo Xiao, Arul M. Chinnaiyan. Investigating the intrinsic epigenetic dependencies of estrogen receptor positive and ESR1 mutant breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5290.