Roles of BRCA1 transcription target genes in tumorigenesis and aging

点击翻译按钮获取中文摘要

My laboratory has been investigating functions of the breast cancer associated gene 1 (BRCA1), p53, and Sirtuins in cancer, metabolism and aging. Germline mutations of BRCA1 are responsible for about 40% of cases of familiar human breast cancer. Mutations in BRCA1 are also responsible for 90% of cases of the combined familiar breast-ovarian cancer syndrome. Analyzing mouse models carrying various mutations, including isoform, null, point, hypomorphic and conditional knockout of BRCA1 generated by gene targeting, we have elucidated many of the fundamental mechanisms underlying BRCA1 associated tumorigenesis. We found that BRCA1-associated tumorigenesis is accompanied by massive genetic instability and p53 mutations, which markedly accelerates cancer initiation and growth. To illustrate the underlying mechanism, we demonstrated that BRCA1 plays an essential role in maintaining genome integrity; therefore BRCA1-deficiency alone does not cause tumor formation, instead, it triggers genetic instability, which eventually results in tumorigenesis after acquiring further permissive alterations, primarily p53 inactivation. These studies provided the first direct genetic evidence that p53 is involved in BRCA1-associated cancer. These mouse models are pivotal for the testing of drugs to prevent human cancers, and for testing the role of various agents, such as radiation, environment stress oncogenes, estrogens, and carcinogens in tumor initiation and growth. BRCA1 also positively regulates transcription of several members of the Sirtuin family, which serve as histone and protein deacetylases. We have generated and analyzed many Sirtuin mutant mice and found that loss of functions of SIRT1, 2, 3, and 4 results in tumorigenesis. Besides cancer, sirtuin mutant mice also displayed abnormalities in metabolic processes, including gluconeogenesis, glycolysis, fat metabolism, triglyceride synthesis, insulin sensitivity, diabetes, and/or premature aging. Thus, Sirtuins might serve as a link among cancer, aging and metabolism, which are potential interesting projects for investigation. Currently, we are investigating how the aging and metabolism affect the cancer development, how to increase health lifespan for cancer prevention, and how to effectively treat cancers based on our knowledge from studying BRCA1 and sirtuins.