Abstract Breast cancer is one of the most prevalent malignant tumors globally and a leading cause of cancer-related mortality among women. Estrogen receptor (ER) positive breast cancer accounts for approximately 70% of all cases. Endocrine therapy targeting estrogen receptors is a cornerstone of clinical treatment for ER-positive breast cancer; however, the emergence of resistance during therapy significantly undermines its therapeutic efficacy ERα is a key factor in the initiation and progression of ER-positive breast cancer and serves as the primary target for endocrine therapies. In this study, we identified a novel ERα co-regulator, SMARCD3, a member of the SMARCD family within the SWI/SNF chromatin remodeling complex. SMARCD3 acts as a tumor suppressor in ER-positive breast cancer, inhibiting tumor progression and enhancing sensitivity to endocrine therapy. Notably, SMARCD3 expression is significantly downregulated in ER-positive breast cancer, and its reduced expression correlates with poor prognosis. Overexpression of SMARCD3 inhibits the proliferation of ER-positive breast cancer cells. Mechanistically, SMARCD3 recruit histone deacetylases HDAC1 and HDAC2, as well as the E3 ubiquitin ligase TRIM21, to form a complex that downregulates ERα-mediated transcriptional activity and reduces ERα protein stability, thus inhibiting ERα function through both transcriptional and post-translational mechanisms. Additionally, we observed that the SWIB domain of SMARCD3 participates in the ubiquitin-mediated degradation of ERα. In summary, our findings identify SMARCD3 as a novel co-suppressor of ERα that inhibits the progression of ER-positive breast cancer and enhances sensitivity to endocrine therapy, providing new insights for therapeutic strategies in ER-positive breast cancer. Citation Format: H. Dong, Y. Xu. Smarcd3 co-suppresses erα signaling pathway mediates tumor progression and its role in anti-estrogen resistance in breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-10-15.
Dong et al. (Tue,) studied this question.