title: Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer.
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.affiliation: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors.forename: François
authors.initials: F
authors.lastname: Vaillant
authors.forename: Delphine
authors.initials: D
authors.lastname: Merino
authors.forename: Lily
authors.initials: L
authors.lastname: Lee
authors.forename: Kelsey
authors.initials: K
authors.lastname: Breslin
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Pal
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Ritchie
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Michael
authors.initials: M
authors.lastname: Christie
authors.forename: Louisa J
authors.initials: LJ
authors.lastname: Phillipson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.forename: G Bruce
authors.initials: GB
authors.lastname: Mann
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009596:Nitrophenols / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000032:analysis*; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009596:Nitrophenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C579720:venetoclax