Abstract
Breast cancer (BRCA) remains a global health burden, with endocrine-resistant ER-positive BRCA posing therapeutic challenges. This study investigates STAMBP's role in breast cancer progression and evaluates its potential as a therapeutic target. Through siRNA library screening in ER-positive cell lines, we identified STAMBP as a key regulator of ERα signaling and observed its upregulation in BRCA samples. (fold changes > 2, sample sizes = 30, p < 0.001), particularly in ER-positive subtypes. Prognostic analysis demonstrated that STAMBP overexpression correlates with poor clinical outcomes in ER-positive BRCA patients (p < 0.05). In vitro functional assays showed STAMBP promoted proliferation, metastasis, and epithelial-mesenchymal transition of ER-positive cells by regulating the activity of ERα signaling. Mechanistically, the deubiquitinase STAMBP directly reduces the K48-linked polyubiquitination levels of ERα, enhancing its protein stability and activating downstream oncogenic signaling. STAMBP knockdown restored tamoxifen sensitivity in endocrine-resistant BRCA cells by reducing ERα stability. This study has certain limitations, including the absence of pharmacological validation and reliance on small, single-center clinical cohorts, which should be addressed in future research to further substantiate the clinical relevance of targeting STAMBP in BRCA. Collectively, our findings identified STAMBP as a prognostic marker and demonstrated its dual role in driving ER-positive BRCA malignancy and mediating endocrine resistance. Targeting STAMBP may represent an innovative approach to improve endocrine therapeutic efficacy in ER-positive BRCA.