5-androstene 3β,17α diol induces autophagic cell death of human breast cancer cells and enhances radiation cytotoxicity

Herein, we demonstrate that the steroid, 5-androstene 3β,17α diol (17α-AED) induced cell death in human breast cancer cells MCF-7, MDA-MB231, T47D and TTU-1 at clinically relevant levels. 17α-AED treatment resulted in autophagic cell death without evidence of apoptosis in breast cancer cells revealed by increased cleavage of microtubule-associated proteinlight chain 3 and the presence of acidic vesicular organelles in the absence of caspase 3, 8 or 9 activation and PARP processing. Increased phosphorylation of eukaryotic translational initiation factor 2α (eIF2α) was detected in treated MCF-7 cells and disruption of eIF2α signaling reduced autophagic cell death in 17α-AED treated MCF-7 cells. In breast cancer cell survival studies, 17α-AED synergistically potentiated the cytotoxicity of radiation treatment. Collectively, 17α-AED induces autophagic cell death in human breast tumors which is mediated, at least in part, by eIF2α signaling and may have potential therapeutic value for the treatment of breast tumors.