Biomaterial Database

Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. 2012

Samantha R Oakes, and François Vaillant, and Elgene Lim, and Lily Lee, and Kelsey Breslin, and Frank Feleppa, and Siddhartha Deb, and Matthew E Ritchie, and Elena Takano, and Teresa Ward, and Stephen B Fox, and Daniele Generali, and Gordon K Smyth, and Andreas Strasser, and David C S Huang, and Jane E Visvader, and Geoffrey J Lindeman

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.

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.

UI	MeSH Term	Description	Entries
D008565	Membrane Proteins	Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.	Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D009596	Nitrophenols	PHENOLS carrying nitro group substituents.	Nitrophenol
D010879	Piperazines	Compounds that are derived from PIPERAZINE.
D011518	Proto-Oncogene Proteins	Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.	Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D012074	Remission Induction	Therapeutic act or process that initiates a response to a complete or partial remission level.	Induction of Remission,Induction, Remission,Inductions, Remission,Remission Inductions
D001943	Breast Neoplasms	Tumors or cancer of the human BREAST.	Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072224	Bcl-2-Like Protein 11	A BCL-2-like protein that has a C-terminal BCL-2 homology (BH3) domain and forms heterodimers with other BCL-2 FAMILY PROTEINS. It is a strong inducer of APOPTOSIS and ANOIKIS; several isoforms are expressed (BimEL, Bim L, Bim-alpha, Bim-s; and Bim-gamma) that have different potencies for inducing apoptosis.	BCL2L11 Protein,BIM Protein,Bcl-2-Binding Protein, BIM,Bcl-2-Interacting Mediator of Cell Death,11, Bcl-2-Like Protein,BIM Bcl-2-Binding Protein,Bcl 2 Binding Protein, BIM,Bcl 2 Interacting Mediator of Cell Death,Bcl 2 Like Protein 11,Protein 11, Bcl-2-Like,Protein, BCL2L11,Protein, BIM,Protein, BIM Bcl-2-Binding
D000077143	Docetaxel	A semisynthetic analog of PACLITAXEL used in the treatment of locally advanced or metastatic BREAST NEOPLASMS and NON-SMALL CELL LUNG CANCER.	Docetaxel Anhydrous,Docetaxel Hydrate,Docetaxel Trihydrate,Docetaxol,N-Debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol,NSC 628503,RP 56976,RP-56976,Taxoltere Metro,Taxotere,N Debenzoyl N tert butoxycarbonyl 10 deacetyltaxol,RP56976