Homer3 Promotes Aggressive Phenotypes in Triple-Negative Breast Cancer Through Cell Cycle- and MYC-Associated Programs.

Homer proteins (Homer1-3) are scaffold proteins that mediate protein-protein interactions in signal transduction; however, the role of Homer3 in breast cancer (BC), particularly triple-negative breast cancer (TNBC), remains poorly defined. Here, we investigated the clinical relevance and functional significance of Homer3 in BC and TNBC. Publicly available datasets from TCGA and GEO were analyzed to evaluate associations between Homer3 expression and patient outcomes using Kaplan-Meier survival analysis. Pathway enrichment analysis and gene set variation analysis (GSVA) were performed to identify signaling programs associated with Homer3 co-expressed genes. Functional roles were examined using stable TNBC cell lines with Homer3 knockdown or overexpression, followed by assays for cell proliferation, clonogenic growth, migration, invasion, and wound healing. We found that Homer3 expression was elevated in breast tumors compared with normal tissues and was associated with poor prognosis in both BC and TNBC. Homer3 expression was higher in TNBC than in non-TNBC subtypes and negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. Functionally, Homer3 depletion suppressed TNBC cell proliferation, clonogenic capacity, migration, invasion, and wound healing, whereas Homer3 overexpression produced reciprocal effects. Pathway analyses revealed that Homer3 co-expressed genes were enriched in cell cycle-related pathways and Hallmark MYC signaling, which were associated with adverse clinical outcomes. Consistently, Homer3 knockdown selectively reduced key proliferative cell-cycle regulators. Collectively, these findings demonstrate that Homer3 is associated with aggressive phenotypes and MYC- and cell cycle-linked proliferative programs in breast cancer, particularly in TNBC. Survival analyses are presented as exploratory findings, supporting the biological relevance of Homer3 in TNBC. These findings suggest that Homer3 may represent a potential therapeutic vulnerability.