The Sigma-1 Gene as a Prognostic Marker in Chemotherapy-Treated Breast Cancer-Antagonists' Synergism With Paclitaxel In Vitro.

BACKGROUND: Treatment benefits of paclitaxel (Px)-based chemotherapy are often offset by dose-limiting side effects. The sigma-1 receptor (Sig1R) is implicated in chemotherapy (ChT)-induced neuropathy but its role in the metastatic potential of breast cancer (BCa) has not been properly explored. METHODS: This work investigated the predictive and prognostic value of Sig1R gene (S1R) expression for pathologic complete response (pCR) and distant relapse-free survival (DRFS) following neoadjuvant ChT (nChT). We further examined the anticancer efficacy of the Sig1R antagonists IPAG and BD1047 in combination with Px in triple-negative breast cancer (TNBC) cell lines. RESULTS: We report that S1R positively associated with pCR in two patient cohorts. Upregulated gene clusters in high-S1R samples of the pCR group are associated with ontology terms related to cell division, DNA replication and microtubule dynamics. High S1R expression was also associated with poor DRFS in TNBC patients. Sig1R knockdown (Sig1R-KD) in MDA-MB-231 and HCC1806 cell lines reduced clonogenic proliferation while treatment with Sig1R antagonists IPAG or BD1047 decreased cell motility. Sig1R-KD decreased Px-induced apoptosis; the synergistic effects of Px in combination with IPAG or BD1047 were evaluated by the Chou-Talalay method. Cytotoxic and antimotility effects of Px were enhanced when combined with Sig1R antagonists. CONCLUSION: Taken together, our results indicate that S1R is a potential biomarker for the response to nChT and that targeting Sig1R could enhance Px efficacy while deterring key metastatic mechanisms.