Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer
- Author(s)
- Vaillant, F; Merino, D; Lee, L; Breslin, K; Pal, B; Ritchie, ME; Smyth, GK; Christie, M; Phillipson, LJ; Burns, CJ; Mann, GB; Visvader, JE; Lindeman, GJ;
- Details
- Publication Year 2013-07-08,Volume 24,Issue #1,Page 120-129
- Journal Title
- CANCER CELL
- Publication Type
- Journal Article
- Abstract
- The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.
- Publisher
- CELL PRESS
- Keywords
- CHRONIC LYMPHOCYTIC-LEUKEMIA; SURVIVAL SIGNALS; CELL-DEATH; THERAPY; FAMILY; INHIBITOR; TUMORS; NAVITOCLAX; ABT-737; ACTIVATION
- Research Division(s)
- Stem Cells And Cancer; Molecular Medicine; Bioinformatics; Systems Biology And Personalised Medicine; Chemical Biology
- Publisher's Version
- https://doi.org/10.1016/j.ccr.2013.06.002
- NHMRC Grants
- NHMRC/461221, NHMRC/1016701,
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Creation Date: 2013-07-08 12:00:00