Ezrin (EZR) promotes breast cancer progression and drug resistance: Molecular mechanisms involving STAT3 activation.

AIMS: To define the clinical relevance and mechanistic role of Ezrin (EZR) in breast cancer progression, metastasis, and paclitaxel resistance.

MATERIALS AND METHODS: We integrated public expression/survival datasets with tissue immunohistochemistry, and used stable EZR silencing in MDA-MB-231 cells combined with phenotypic assays, phospho-kinase profiling with immunoblot validation and STAT3 activation rescue, plus orthotopic xenograft and experimental lung colonization models; paclitaxel-resistant sublines were generated to test chemoresistance.

KEY FINDINGS: EZR was overexpressed in breast cancer and correlated with poorer overall survival (HR = 1.21, p = 0.048), with high EZR detected in 55.6% (20/36) of tumours in our cohort. EZR depletion reduced proliferation and migration/invasion while inducing apoptosis, and suppressed tumour growth and lung metastasis in vivo. Mechanistically, EZR sustained STAT3 Tyr705 phosphorylation and downstream pro-survival outputs, implicating cytoskeletal coupling; STAT3 activation partially rescued EZR-loss phenotypes. EZR was elevated in paclitaxel-resistant cells, and EZR knockdown increased paclitaxel sensitivity.

SIGNIFICANCE: EZR links cytoskeletal remodeling to STAT3 signalling to drive metastatic competence and paclitaxel resistance, nominating EZR as a potential therapeutic vulnerability in treatment-refractory breast cancer.