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

Background: Estrogen receptor alpha (ERalpha) 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 ERalpha, 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.