MTDH∆7-mediated mTOR activation drives doxorubicin resistance in triple-negative breast cancer: Relevance of mTORC1 inhibition on chemosensitization

Cancer chemoresistance poses a major hurdle in the management of several cancers, including breast cancer. Herein, we identified MTDH∆7, a splice variant of an oncogene, metadherin (MTDH), promotes doxorubicin (Dox)-induced chemoresistance in triple-negative breast cancer (TNBC) cells. Increased MTDH∆7 levels were positively correlated with the elevated levels of ABC transporters like ABCB1, ABCC1, and ABCG2, which in turn caused reduced intracellular Dox accumulation. Interestingly, everolimus, an mTORC1 inhibitor, potentiated Dox-induced cytotoxicity by inhibiting MTDH∆7-mediated increase in the aforementioned ABC transporters. Moreover, MTDH∆7 overexpression increased mTORC1 levels, possibly due to MTDH∆7-induced accentuation of mitochondrial respiration, ATP production, and AMPK inactivation. Mechanistically, enhanced phosphorylation of mTORC1 caused NF-κB-dependent activation of cAMP-regulatory element-binding protein (CREB). Further, activated CREB led to an increase in the levels of ABCB1, ABCC1, and ABCG2. Inhibition of either mTORC1 by everolimus or NF-κB by BAY-11-7082 or CREB by H89 reversed these effects and mitigated MTDH∆7-mediated Dox efflux. Accordingly, while Dox administration alone marginally caused tumor regression in SCID mice bearing LV.MTDH∆7-MDA-MB-231 cells, administration of everolimus greatly sensitized these mice to Dox-induced tumor regression. In agreement, intriguingly, a positive correlation was observed between elevated MTDH∆7, mTORC1 activation, and ABC transporters level in human breast cancer patient cohort tumor samples. Collectively, MTDH∆7, by promoting mTOR signaling causes breast cancer chemoresistance, and that targeting MTDH∆7-mTOR signaling axis effectively enhances chemosensitization.