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.
Subject(s)
Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Estrogens , Molecular Targeted Therapy , Neoplasm Proteins/antagonists & inhibitors , Neoplasms, Hormone-Dependent/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis Regulatory Proteins/physiology , Biomarkers, Tumor , Breast/growth & development , Breast/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Carcinoma/genetics , Carcinoma/pathology , Drug Design , Drug Synergism , Female , Gene Expression Regulation, Neoplastic , Genes, bcl-2 , Humans , Mice , Mitochondria/drug effects , Mitochondria/physiology , Multigene Family , Neoplasm Proteins/genetics , Neoplasms, Hormone-Dependent/genetics , Peptide Fragments/chemistry , Prognosis , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/physiology , Receptors, Estrogen/analysis , Signal Transduction/drug effects , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: The main aim of this study was to determine the understanding and perception of parents following the diagnosis of a minor cardiac abnormality, namely a small ventricular septal defect, in the child. Other aims included discovering the reasons behind these perceptions and whether they affected the parents' management of their child and his/her cardiac problem. METHODS: Fifty-six infants and children from two tertiary centres and the private practices of the participating cardiologists were enrolled over a 5-month period. Questionnaires were prepared and distributed to all their parents. RESULTS: Complete data was obtained from 40 parents. Close to 80% of the parents perceived the small ventricular septal defect as a minor problem and most understood the nature of the defect. However, when asked about precautions for their child, only two-thirds recalled the need for antibiotic prophylaxis. Most parents experienced distress and anxiety when told initially of the diagnosis but none reportedly restricted their child's physical activity. CONCLUSIONS: Most parents have a clear understanding and perception of their child's small ventricular septal defect. There is a need for further improvement to facilitate parental understanding, especially with regard to the need for antibiotic prophylaxis.
