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Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737.

Authors
  • Oakes, Samantha R
  • Vaillant, François
  • Lim, Elgene
  • Lee, Lily
  • Breslin, Kelsey
  • Feleppa, Frank
  • Deb, Siddhartha
  • Ritchie, Matthew E
  • Takano, Elena
  • Ward, Teresa
  • Fox, Stephen B
  • Generali, Daniele
  • Smyth, Gordon K
  • Strasser, Andreas
  • Huang, David C S
  • Visvader, Jane E
  • Lindeman, Geoffrey J
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Feb 21, 2012
Volume
109
Issue
8
Pages
2766–2771
Identifiers
DOI: 10.1073/pnas.1104778108
PMID: 21768359
Source
Medline
License
Unknown

Abstract

Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2-expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2-expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.

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