The primary interest of my group is mouse genetics and mammary gland tumorigenesis using animal model systems. We have been studying three groups of genes, including functions of fibroblast growth factor receptors (FGFRs), Smad genes, and breast tumor suppressor gene (BRCA1). We are currently focusing on functional analysis of BRCA1 in cell cycle checkpoint, genetic stability, aging and tumorigenesis. Breast cancer is the most common cancer and the second leading cause of cancer mortality in women, with approximately one in 9 being affected over their lifetime. In the past several years, we have introduced a series of mutations-including a null mutation, an isoform mutation, and a conditional mutation-into the mouse BRCA1 locus. Mutational analyses at both cellular and whole animal levels demonstrated that the primary function of BRCA1 is to maintain genome integrity through its control over the G2-M cell cycle checkpoint, spindle checkpoint, and centrosome duplication. BRCA1 mutations result in genetic instability, which then activates cellular protection mechanisms, including cell-cycle checkpoints and programmed cell death, to eliminate the mutant cells. This is why BRCA1 mutant cells fail to grow in culture. On the other hand, the genetic instability in BRCA1 mutant cells theoretically increases mutation rates of all genes, including tumor suppressors and oncogenes, which ultimately overcomes the proliferation defects caused by the BRCA1 loss and results in tumor formation. We are continuing to study mechanisms of BRCA1 associated tumorigenesis and seeking efficient ways of prevention and therapeutic treatment of this deadly disease.
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