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Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer.
- Source :
-
Cancer cell [Cancer Cell] 2013 Jul 08; Vol. 24 (1), pp. 120-9. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Biphenyl Compounds pharmacology
Breast Neoplasms chemistry
Breast Neoplasms pathology
Female
Humans
Mice
Mice, SCID
Nitrophenols pharmacology
Phosphoinositide-3 Kinase Inhibitors
Piperazines pharmacology
TOR Serine-Threonine Kinases antagonists & inhibitors
Xenograft Model Antitumor Assays
Breast Neoplasms drug therapy
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Receptors, Estrogen analysis
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 23845444
- Full Text :
- https://doi.org/10.1016/j.ccr.2013.06.002