Breast cancer patients are commonly treated with taxane (e.g. docetaxel) chemotherapy, despite poor outcomes and eventual disease relapse. We previously identified the Bcl-2-associated death promoter (BAD) as a prognostic indicator of good outcome in taxane-treated breast cancer patients. We also demonstrated that BAD expression in human breast carcinoma cells generated larger tumors in mouse xenograft models. These paradoxical results suggest that BAD-expressing tumors are differentially sensitive to taxane treatment. We validated this here and show that docetaxel therapy preferentially reduced growth of BAD-expressing xenograft tumors. We next explored the cellular mechanism whereby BAD sensitizes cells to docetaxel. Taxanes are microtubule inhibiting agents that cause cell cycle arrest in mitosis whereupon the cells either die in mitosis or aberrantly exit (mitotic slippage) and survive as polyploid cells. In response to docetaxel, BAD-expressing cells had lengthened mitotic arrest with a higher proportion of cells undergoing death in mitosis with decreased mitotic slippage. Death in mitosis was non-apoptotic and not dependent on Bcl-XL interaction or caspase activation. Instead, cell death was necroptotic, and dependent on ROS. These results suggest that BAD is prognostic for favourable outcome in response to taxane chemotherapy by enhancing necroptotic cell death and inhibiting the production of potentially chemoresistant polyploid cells.

The Bcl-2-associated death promoter BAD is a prognostic indicator for good clinical outcome of breast cancer patients; however, whether BAD affects breast cancer biology is unknown. Here we showed that BAD increased cell growth in breast cancer cells through two distinct mechanisms. Phosphorylation of BAD at S118 increased S99 phosphorylation, 14-3-3 binding and AKT activation to promote growth and survival. Through a second, more prominent pathway, BAD stimulated mitochondrial oxygen consumption in a novel manner that was downstream of substrate entry into the mitochondria. BAD stimulated complex I activity that facilitated enhanced cell growth and sensitized cells to apoptosis in response to complex I blockade. We propose that this dependence on oxidative metabolism generated large but nonaggressive cancers. This model identifies a non-canonical role for BAD and reconciles BAD-mediated tumor growth with favorable outcomes in BAD-high breast cancer patients.