Roles of BRCA1 transcription target genes in tumorigenesis and aging

我的实验室一直在研究乳腺癌相关基因1(BRCA1)、p53和sirtuins在癌症、新陈代谢和衰老中的功能。 BRCA1的胚系突变导致了大约40%的常见人类乳腺癌病例。BRCA1的突变也是90%的常见乳腺癌-卵巢癌综合征合并病例的原因。通过分析携带各种突变的小鼠模型，包括由基因打靶产生的BRCA1的同型、零、点、亚型和条件性敲除，我们已经阐明了BRCA1相关肿瘤发生的许多基本机制。我们发现BRCA1相关的肿瘤发生伴随着大量的遗传不稳定和P53突变，这显著地加速了癌症的启动和生长。为了阐明潜在的机制，我们证明了BRCA1在维持基因组完整性方面起着至关重要的作用；因此，BRCA1缺乏本身并不会导致肿瘤的形成，相反，它会触发遗传不稳定性，最终导致在获得进一步允许的改变(主要是P53失活)后导致肿瘤的发生。这些研究提供了第一个直接的遗传学证据，表明P53与BRCA1相关的癌症有关。这些小鼠模型对于测试预防人类癌症的药物，以及测试各种因素，如辐射、环境应激癌基因、雌激素和致癌物在肿瘤起始和生长中的作用是至关重要的。BRCA1还正向调节Sirtuin家族中几个成员的转录，这些成员充当组蛋白和蛋白质脱乙酰酶。我们已经培育并分析了许多Sirtuin突变小鼠，发现SIRT1、2、3和4功能的丧失会导致肿瘤的发生。除了癌症，sirtuin突变小鼠还表现出代谢过程的异常，包括糖异生、糖酵解、脂肪代谢、甘油三酯合成、胰岛素敏感性、糖尿病和/或过早衰老。因此，sirtuins可能是癌症、衰老和新陈代谢之间的联系，这是潜在的有趣的研究项目。目前，我们正在研究衰老和代谢如何影响癌症的发展，如何延长癌症预防的健康寿命，以及如何根据我们通过研究BRCA1和sirtuins所获得的知识有效地治疗癌症。

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.