BAD sensitizes breast cancer cells to docetaxel with increased mitotic arrest and necroptosis

Abstract

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. Triple-negative breast cancer patients receive taxane chemotherapy, such as docetaxel (Taxotere ®), as standard first-line treatment despite an overall poor prognosis, high rate of relapse, and adverse effects 1. While multiple causes of cellular taxane resistance are known, these have not yet provided clinical markers to guide taxane therapy decisions 2-4. Understanding the molecular mechanisms that mediate outcome to taxane therapy may identify predictive biomarkers and novel therapeutic targets. The Bcl-2 family member BAD (Bcl-2-associated death promoter) is a prognostic indicator for good clinical outcome of taxane-treated breast cancer patients 5. BAD modulates breast cancer cell proliferation and tumor progression by regulating cell cycle progression 6,7. Thus, understanding how BAD better predicts patient outcome could aid in understanding docetaxel chemoresistance. Taxanes are anti-mitotic drugs that perturb microtubule dynamics, leading to chronic activation of the spindle assembly checkpoint and inhibition of the anaphase promoting complex that delays the degradation of cyclin B1 and inhibits mitotic exit 8. Ideally, this aberrant mitotic arrest initiates cell death in mitosis by facilitating the accumulation of a caspase-dependent death signal 9. Often, however, cells degrade sufficient cyclin B1 prior to full activation of apoptotic caspases, and cells slip out of mitosis in the absence of cytokinesis and enter G1 as polyploid cells. These polyploid cells have differential fates of G1 arrest, post-mitotic death, or continued cell cycle progression 10,11. The su...

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