title: Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737.
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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052,  Australia.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Oakes
authors.forename: François
authors.initials: F
authors.lastname: Vaillant
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.forename: Lily
authors.initials: L
authors.lastname: Lee
authors.forename: Kelsey
authors.initials: K
authors.lastname: Breslin
authors.forename: Frank
authors.initials: F
authors.lastname: Feleppa
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Ritchie
authors.forename: Elena
authors.initials: E
authors.lastname: Takano
authors.forename: Teresa
authors.initials: T
authors.lastname: Ward
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012074:Remission Induction; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D043823:Taxoids; D051020:bcl-X Protein; D000077143:Docetaxel