Breast cancer is the most common cancer. It is the second leading cause of cancer mortality among women in Western countries, with approximately one in eight being affected during their lifetime. Approximately 90 percent of breast cancers are sporadic, while the remaining 10 percent are inheritable. Germline mutations in the breast-cancer-associated gene 1 (BRCA1) have been detected in approximately 40 percent of familial breast cancer and 90 percent of combined familial breast-ovarian cancers. Analyzing mouse models carrying various mutations, including isoform, null, point, hypomorphic, and conditional knockout of BRCA1 generated by gene targeting, our lab elucidated many of the fundamental mechanisms underlying BRCA1ssociated 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 potentially interesting projects for investigation. Currently, we are investigating how aging and metabolism affect cancer development, how to increase health lifespan for cancer prevention, and how to treat cancers effectively based on the knowledge gained from studying BRCA1 and Sirtuins.
Studies should focus on offering a more detailed molecular analysis, stronger signaling transduction, lineage tracing, target identification, therapeutic drug development, and more extensive clinical trials.