Tamoxifen Regulates Cell Fate Through Mitochondrial Estrogen Receptor Beta in Breast Cancer

Tamoxifen has both cytostatic and cytotoxic properties for breast cancer. Tamoxifen engaged mitochondrial estrogen receptor beta (ERβ) as an antagonist in MCF-7 BK cells, increasing reactive oxygen species (ROS) concentrations from the mitochondria that were required for cytotoxicity. In part this derived from tamoxifen down-regulating manganese superoxide dismutase (MnSOD) activity through nitrosylating tyrosine 34, thereby increasing ROS. ROS activated protein kinase C delta and c-jun N-terminal kinases, resulting in the mitochondrial translocation of Bax and cytochrome C release. Interestingly, tamoxifen failed to cause high ROS levels or induce cell death in MCF7BK-TR cells due to stimulation of MnSOD activity through agonistic effects at mitochondrial ERβ. In several mouse xenograft models, lentiviral shRNA-induced knockdown of MnSOD caused tumors that grew in the presence of tamoxifen to undergo substantial apoptosis. Tumor MnSOD and mitochondrial ERβ are therefore targets for therapeutic intervention to reverse tamoxifen resistance and enhance a cell death response.