SIRT7 Orchestrates Ligand‐Dependent ERα Signaling Rewiring to Drive Tamoxifen Resistance in ERα‐positive Breast Cancer

ABSTRACT Tamoxifen resistance (TAMR) remains a major clinical challenge in the treatment of ERα‐positive breast cancer. Although ERα loss and activation of alternative survival pathways are well‐known contributors, the mechanisms underlying ERα dysregulation and signaling rewiring remain incompletely understood. Here, we show that SIRT7 is markedly upregulated in TAMR cells and patient‐derived xenografts (PDXs), and that its depletion significantly suppresses TAMR phenotypes. Mechanistically, SIRT7‐mediated deacetylation of ERα at lysines 302 and 303 facilitates its dissociation from the HSP90 chaperone complex and subsequent recognition by the E3 ubiquitin ligase CHIP, resulting in K48‐linked polyubiquitination and proteasomal degradation of ERα. This mechanism underlies the context‐dependent dual role of SIRT7: In tamoxifen‐sensitive breast cancer, SIRT7 suppresses canonical ERα signaling and restrains tumor growth by accelerating ERα degradation, which promotes the development of estrogen‐independent progression. By contrast, under tamoxifen treatment, the interaction between SIRT7 and ERα is enhanced, which unexpectedly redirects deacetylated ERα toward activation of EGFR signaling and thereby drives therapeutic resistance. Notably, pharmacological inhibition of SIRT7 with compound 97491 induces pronounced regression of TAMR‐derived xenografts. Collectively, these findings establish SIRT7 as a central regulator of ERα signaling and a promising therapeutic target for overcoming endocrine resistance in breast cancer.