Mcl-1 Drives Resistance of Estrogen Receptor-α Positive Breast Cancers to Targeted Therapies

Abstract

Evasion of cell death is essential to every step of tumorigenesis. Anti-apoptotic Bcl-2 family proteins are master inhibitors of cell death, and thus are often overexpressed in cancers. In particular, Bcl-2, Bcl-xL, and Mcl-1 are highly expressed in Estrogen Receptor-alpha positive (ERα+) breast cancers. However, one anti-apoptotic Bcl-2 family protein, Mcl-1, is understudied in ERα+ breast cancers. Herein we show that Mcl-1 is essential to ERα+ breast tumor cell survival, and is a more potent tumor cell survival factor than other family members, like Bcl-2 and Bcl-xL. Interestingly, Mcl-1 expression and activity increased upon Bcl-2/Bcl-xL dual inhibition with ABT-263, mediated by increased Mcl-1 cap-dependent translation. Blockade of cap-dependent translation, through inhibition of mTORC1 signaling, resulted in tumor cell killing in cell culture and in vivo, phenocopying ablation of Mcl-1 by RNA-interference. Mcl-1 depletion in combination with ABT-263 restored sensitivity to Bcl-2/Bcl-xL blockade, suggesting that Mcl-1 is a primary resistance factor to Bcl-2/Bcl-xL inhibition in ERα+ breast cancers. Importantly, preliminary studies suggest that anti-apoptotic Bcl-2 family proteins can promote resistance to standard of care breast cancer therapies. Mcl-1 inhibition, but not Bcl-2/Bcl-xL blockade, promoted cell death in a model of anti-estrogen resistance, long term estrogen deprivation (LTED). Mcl-1 inhibition using polymeric nanoparticles containing Mcl-1 siRNA (si-NPs), increased tumor cell death in combination with LTED and after treatment with the selective estrogen receptor downregulator fulvestrant. Therefore, Mcl-1 is a dominant tumor cell survival factor in ERα+ breast cancers that is rapidly and potently upregulated in response to targeted therapies. However, dependence on Mcl-1 for tumor cell survival may be clinically thwarted using mTOR inhibitors or si-NPs.