Journal
CANCER CELL
Volume 24, Issue 1, Pages 120-129Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2013.06.002
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Funding
- National Health and Medical Research Council, Australia (NHMRC) [461221, 1016701]
- NHMRC IRIISS
- Victorian State Government through Victorian Cancer Agency
- Australian Cancer Research Foundation
- National Breast Cancer Foundation (NBCF)
- Qualtrough Family Bequest
- NHMRC Australia Fellowship
- NBCF Early Career Fellowship
- National Breast Cancer Foundation [NC-13-21, ECF-13-06] Funding Source: researchfish
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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.
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