Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer
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
WEHI Research Division(s)
Stem Cells And Cancer; Molecular Medicine; Bioinformatics; Systems Biology And Personalised Medicine; Chemical Biology
NHMRC Grants
NHMRC/461221 NHMRC/1016701
Rights Notice
Copyright © 2013 Elsevier B.V. All rights reserved. ScienceDirect® is a registered trademark of Elsevier B.V.


Creation Date: 2013-07-08 12:00:00
Last Modified: 0001-01-01 12:00:00
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