Ceramide Synthase 6 Mediates Triple-Negative Breast Cancer Response to Chemotherapy Through RhoA- and EGFR-Mediated Signaling Pathways

PURPOSE: Limited treatment options and lack of treatment sensitivity biomarkers make the clinical management of triple-negative breast cancer (TNBC) challenging. Ceramide synthase 6 (CERS6) generates ceramides, which are key intermediates in sphingolipid biosynthesis and play important roles in cancer progression and resistance. METHODS: CERS6 was analyzed to determine its potential as a treatment sensitivity biomarker. CERS6 levels were determined in patients with breast cancer, and the roles and downstream signaling of CERS6 were analyzed using cellular and biochemical assays. RESULTS: Analysis of CERS6 expression in 195 patients with TNBC and their clinical response to chemotherapy revealed that individuals with CERS6 overexpression experienced significantly inferior responses to chemotherapy than those without CERS6 overexpression. Functional analysis demonstrated that although CERS6 overexpression did not affect TNBC cell growth and migration, it conferred chemoresistance. CERS6 inhibition significantly reduced growth, migration, and survival by suppressing the RhoA- and EGFR-mediated signaling pathways. Compared to control cells, CERS6-depleted cells were consistently less viable at different concentrations of chemotherapeutic agents. CONCLUSION: Our study is the first to demonstrate that CERS6 may serve as a treatment sensitivity biomarker in patients with TNBC in response to chemotherapy. In addition, our findings suggested that CERS6 may be a therapeutic target for TNBC treatment.