Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer

• Published in: Oncogene Vol. 35; no. 15; pp. 1877 - 1887
• Main Authors: Merino, D, Lok, S W, Visvader, J E, Lindeman, G J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.04.2016; Nature Publishing Group
• Subjects: 631/67/1347; Aniline Compounds - pharmacology; Aniline Compounds - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - physiology; Bax protein; Bcl-2 protein; Bcl-x protein; BIM protein; Biomarkers, Tumor; Breast - growth & development; Breast - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - pathology; Cell Biology; Cell death; Chemotherapy; Cytotoxicity; Development and progression; Drug Design; Drug Synergism; Estrogen receptors; Estrogens; Female; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Genetic aspects; Human Genetics; Humans; Innovations; Internal Medicine; Mammary gland; Mcl-1 protein; Medicine; Medicine & Public Health; Mice; Mitochondria - drug effects; Mitochondria - physiology; Molecular Targeted Therapy; Multigene Family; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - genetics; Oncology; Peptide Fragments - chemistry; Prognosis; Properties; Proteins; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - physiology; Receptors, Estrogen - analysis; review; Signal Transduction - drug effects; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TOR Serine-Threonine Kinases - antagonists & inhibitors; Tumor proteins; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.287

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-X L 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.