The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

Craik, A C; Veldhoen, Richard A.; Czernick, M; Buckland, Timothy W.; Kyselytzia, K; Ghosh, Sunita; Lai, Raymond; Damaraju, S.; Underhill, D. Alan; Mackey, John R.; Goping, Ing Swie

doi:10.1038/onc.2010.272

Cited by 31 publications

(25 citation statements)

References 64 publications

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“…This cohort is referred to as Dataset-1 in this study. For Dataset-2, tissue microarrays (TMA) were generated from formalin fixed tumor samples obtained for 152 primary breast cancer patients as described previously [55]. Briefly, the TMA was prepared by punching at least two representative tumor cores from pre-treatment formalin fixed paraffin embedded (FFPE) blocks and embedding them in recipient paraffin blocks.…”

Section: Methodsmentioning

confidence: 99%

The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer

et al. 2016

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Breast cancer is the leading cause of cancer-associated deaths in women worldwide. Clinical biomarkers give information on disease progression and identify relevant biological pathways. A confounding factor that uncouples markers from disease outcome is the ability of tumor cells to mutate and evade clinical intervention. Therefore, we focussed on apoptotic genes that modulate tumor regression. Using gene and tissue microarray analyses, we identified an association of Bcl-2 interacting killer (Bik) with poor breast cancer prognosis. Bik prognostic ability was independent of Estrogen Receptor/Progesterone Receptor and Her2 status. Additionally, Bik was independent of anti-apoptotic Bcl-2, Bcl-xL, Mcl-1 and Bcl-w suggesting a complex mechanism of tumor promotion identified by Bik high tumors. Bik also stimulates autophagy, which can contribute to enhanced tumor fitness. We found a significant association between the autophagy marker ATG5 and Bik. Combined high expression level of ATG5 and Bik was a stronger predictor of outcome than either alone. Thus, our study identifies Bik as a novel, independent prognostic biomarker for poor outcomes in breast cancer and suggests that Bik-mediated autophagy contributes to disease recurrence.

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Section: Methodsmentioning

confidence: 99%

The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer

et al. 2016

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“…[19][20][21] We also showed that BAD promotes prostate tumor growth in mouse models. 22 Clinically, while BAD expression was associated with relapse in tamoxifen-treated breast cancer patients, 23,24 phospho-BAD expression was associated with cisplatin resistance and poor overall survival in ovarian cancer. 25 Our previous findings along with other reports showing the role of BAD in the apoptosis modulation and growth of DC cells 19,22,26 prompted us to explore the potential role of BAD in the biology of CSCs.…”

mentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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“…Our previous results reveal high BAD protein levels are associated with a 3.7-fold increased probability of overall survival of primary breast cancer patients treated with taxane 5 . BAD stimulates cell cycle progression leading to increased breast cancer cell number and tumor growth 7 .…”

Section: Discussionmentioning

confidence: 86%

“…BAD increases sensitivity of breast cancer cells to docetaxel. We had previously shown BADdependent taxane sensitivity in the breast carcinoma cell lines MCF-7 (luminal B), SKBR-3 (HER2) and MDA-MB-468 (TNBC) 5 . To study the structure/function relationship of BAD in docetaxel-treated breast cancer cells, we utilized MDA-MB-231 cells stably expressing ectopic BAD 7 .…”

Section: Resultsmentioning

confidence: 99%

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

Mann

Yang

Montpetit

et al. 2020

Sci Rep

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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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The BH3-only protein Bad confers breast cancer taxane sensitivity through a nonapoptotic mechanism

Cited by 31 publications

References 64 publications

The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer

The pro-apoptotic paradox: the BH3-only protein Bcl-2 interacting killer (Bik) is prognostic for unfavorable outcomes in breast cancer

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

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

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