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Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

2013; Cell Press; Volume: 24; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2013.06.002

1878-3686

François Vaillant, Delphine Mérino, Lily Lee, Kelsey Breslin, Bhupinder Pal, Matthew E. Ritchie, Gordon K. Smyth, Michael Christie, Louisa J. Phillipson, Christopher J. Burns, G. Bruce Mann, Jane E. Visvader, Geoffrey J. Lindeman,

Chronic Lymphocytic Leukemia Research

Summary 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.