Discovery of a Small-Molecule Inhibitor Targeting the ELF3-HSP27 Interaction to Suppress Breast Cancer Progression

Background: Breast cancer remains a leading cause of cancer-related mortality in women, largely due to metastasis and treatment resistance. ELF3, an ETS transcription factor, has been linked to cancer progression; however, the mechanisms regulating its activity remain incompletely understood. Methods: ELF3 expression and its association with patient survival were analyzed using GEO datasets and the Kaplan–Meier Plotter platform. Functional studies were performed using ELF3 knockdown in breast cancer cell lines, followed by WST-1 assays and crystal violet staining. Protein–protein interactions were evaluated using co-expression analysis, immunofluorescence, split luciferase complementation, GST pull-down, and yeast two-hybrid assays. Cycloheximide chase assays were conducted to assess ELF3 protein stability. A panel of small molecules was screened to identify inhibitors of the ELF3-HSP27 interaction, and a lead compound was further validated using biochemical and functional assays. Antitumor activity was evaluated in a xenograft mouse model. Results: High ELF3 expression was associated with poorer overall survival in breast cancer patients. HSP27 was identified as a binding partner that stabilizes ELF3 protein, thereby promoting breast cancer cell proliferation. A novel small-molecule inhibitor disrupting the ELF3-HSP27 interaction suppressed cancer cell growth in vitro and reduced tumor growth in vivo. Conclusions: The ELF3-HSP27 interaction represents a previously unrecognized contributor to breast cancer progression, and its disruption provides a promising therapeutic strategy.