The ELK3-DRP1 axis determines the chemosensitivity of triple-negative breast cancer cells to CDDP by regulating mitochondrial dynamics

Abstract

AbstractTriple-negative breast cancer (TNBC) is the most lethal form of breast cancer. TNBC patients have higher rates of metastasis and restricted therapy options. Although chemotherapy is the conventional treatment for TNBC, the frequent occurrence of chemoresistance significantly lowers the efficacy of treatment. Here, we demonstrated that ELK3, an oncogenic transcriptional repressor that is highly expressed in TNBC, determined the chemosensitivity of two representative TNBC cell lines (MDA-MB231 and Hs578T) to cisplatin (CDDP) by regulating mitochondrial dynamics. We observed that the knockdown of ELK3 in MDA-MB231 and Hs578T rendered these cell lines more susceptible to the effects of CDDP. We further demonstrated that the chemosensitivity of TNBC cells was caused by the CDDP-mediated acceleration of mitochondrial fission, excessive mitochondrial reactive oxygen species production, and subsequent DNA damage. In addition, we identified DNM1L, a gene encoding the dynamin-related protein 1 (a major regulator of mitochondrial fission), as a direct downstream target of ELK3. Based on these results, we propose that the suppression of ELK3 expression could be used as a potential therapeutic strategy for overcoming the chemoresistance or inducing the chemosensitivity of TNBC.