Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer Academic Article uri icon

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.

authors

  • Vaillant, F
  • Merino, D
  • Lee, L
  • Breslin, K
  • Pal, B
  • Ritchie, ME
  • Smyth, GK
  • Christie, M
  • Phillipson, LJ
  • Burns, CJ
  • Mann, GB
  • Visvader, JE
  • Lindeman, GJ

publication date

  • 2013