Journal article
Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer
F Vaillant, D Merino, L Lee, K Breslin, B Pal, ME Ritchie, GK Smyth, M Christie, LJ Phillipson, CJ Burns, GB Mann, JE Visvader, GJ Lindeman
Cancer Cell | CELL PRESS | Published : 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) inhib..
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Awarded by Victorian Cancer Agency
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council, Australia (NHMRC: 461221 and 1016701); NHMRC IRIISS; the Victorian State Government through Victorian Cancer Agency funding of the Victorian Breast Cancer Research Consortium and Operational Infrastructure Support; the Australian Cancer Research Foundation; The National Breast Cancer Foundation (NBCF); and the Qualtrough Family Bequest. J.E.V. was supported by a NHMRC Australia Fellowship, G.K.S. and G.J.L. by NHMRC Research Fellowships, and D.M. by a NBCF Early Career Fellowship.