title: Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer.
abstract: The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.
authors.affiliation: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Merino
authors.affiliation: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: S W
authors.initials: SW
authors.lastname: Lok
authors.affiliation: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Visvader
authors.affiliation: Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Familial Cancer Centre and Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.|Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Lindeman
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D014408:Biomarkers, Tumor; D001940:Breast / Q000254:growth & development / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015195:Drug Design; D004357:Drug Synergism; D004967:Estrogens; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D058990:Molecular Targeted Therapy; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D011960:Receptors, Estrogen / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C474007:Bax protein (53-86); D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004967:Estrogens; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D013449:Sulfonamides; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C579720:venetoclax; C528561:navitoclax