IER5L Facilitates the Progression of Hormone Receptor-Positive Breast Cancer by Inhibiting HSF1 Phosphorylation in Response to Bevacizumab.

Abstract

As the most frequently diagnosed cancer in women worldwide, breast cancer (BC) exhibits high heterogeneity, with hormone receptor-positive (HR+) tumors accounting for 60%-75% of all clinical BC cases. Despite extensive evaluation of bevacizumab (Bev) across BC subtypes, HR + BC remains a major clinical challenge. Given current therapeutic limitations, exploring Bev-related strategies offers promise for uncovering new vulnerabilities in HR + BC. In this study, treatment of the prototypical HR + BC cell line MCF-7 with Bev led to an enhanced invasive phenotype in these cells. Subsequent mRNA sequencing of MCF-7 cells revealed immediate early response 5-like (IER5L) as an upregulated gene in Bev-treated cells. Clinical analysis demonstrated that IER5L expression was significantly elevated in HR + BC tissue samples and that high IER5L levels were closely correlated with TNM stage. Functional characterization revealed that IER5L overexpression enhanced cell migration and invasion, concomitant with the induction of an epithelial-mesenchymal transition (EMT) phenotype. Furthermore, heat-shock factor 1 (HSF1), a known oncogenic driver, showed a positive correlation with IER5L in BC samples, and both proteins co-localized in the nuclear and cytoplasmic compartments. Mechanistically, IER5L suppressed phosphorylation of HSF1 at serine 307, and a phospho‑defective mutant (S307A) significantly enhanced the migratory and invasive phenotypes of BC cells. Collectively, these findings suggest that IER5L contributes to the malignant progression of HR + BC through modulation of HSF1 phosphorylation, thereby providing a promising therapeutic strategy for HR + BC.