Abstract
OBJECTIVE: The ropporin-1 (ROPN1) gene, initially linked to sperm motility, is differentially expressed in triple negative breast cancer (TNBC), suggesting a role in tumor progression and therapy resistance. To characterize ROPN1 expression in breast cancer and evaluate its association with clinicopathological features, survival, and treatment response as a translational biomarker. MATERIALS AND METHODS: Data from The Cancer Genome Atlas (1,087 patients), Sweden Cancerome Analysis Network-Breast (3,273 patients), and geodatabases were analyzed. ROPN1 transcriptional levels were assessed in relation to clinical variables and survival. Chemotherapy agents and epigenetic modulators were tested in cell lines to evaluate ROPN1 regulation. RESULTS: Transcriptional overexpression of ROPN1 was significantly enriched in TNBC/basal-like tumors (p<0.0001) and correlated with reduced overall survival, particularly in basal cases [hazard ratio (HR) = 1.85; 95% confidence interval (CI): 1.02-3.33; p = 0.041]. Patients treated with chemotherapy and exhibiting high ROPN1 levels had unfavorable prognosis, with an even poorer profile in untreated cohorts (HR = 4.55; 95% CI: 1.33-14.29; p = 0.01). Hypomethylation at cg00101712 (HR = 0.59; p = 0.016) and cg09298623 (HR = 0.49; p = 0.0014) CpG sites were associated with worse survival at 5 years follow-up, underscoring epigenetic regulation of this pathway as a key driver of poor outcomes. Furthermore, in vitro treatment with cisplatin, doxorubicin, and paclitaxel resulted in variable responses, with a significant reduction of ROPN1 in HCC70 and HS578T cell lines, while BT549 and MDA-MB-231 cell lines showed notable increases. CONCLUSION: ROPN1 overexpression in TNBC/basal-like tumors suggests a role as a prognostic biomarker and predictor of post-chemotherapy resistance. Investigation of ROPN1 expression in breast tumors may lead to alternative strategies targeting pro-metastatic pathways and improve precision treatment for aggressive breast cancer.