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 to prevent the transformation process from happening.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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Gene and Drug Delivery Systems Study Section (GDD)
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U.S. National Inst Diabetes/Digst/Kidney
United States
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Lahusen, Tyler J; Deng, Chu-Xia (2015) SRT1720 induces lysosomal-dependent cell death of breast cancer cells. Mol Cancer Ther 14:183-92
Cao, Liu; Xu, Xiaoling; Cao, Longyue L et al. (2007) Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach. Carcinogenesis 28:1401-7
Tominaga, Y; Wang, A; Wang, R-H et al. (2007) Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe. Cell Death Differ 14:472-9
Oppermann, Mona; Mizel, Diane; Huang, George et al. (2006) Macula densa control of renin secretion and preglomerular resistance in mice with selective deletion of the B isoform of the Na,K,2Cl co-transporter. J Am Soc Nephrol 17:2143-52
Tominaga, Yohei; Li, Cuiling; Wang, Rui-Hong et al. (2006) Murine Wee1 plays a critical role in cell cycle regulation and pre-implantation stages of embryonic development. Int J Biol Sci 2:161-70
Israelsson, Charlotte; Lewen, Anders; Kylberg, Annika et al. (2006) Genetically modified bone morphogenetic protein signalling alters traumatic brain injury-induced gene expression responses in the adult mouse. J Neurosci Res 84:47-57
Shukla, Vivek; Coumoul, Xavier; Cao, Liu et al. (2006) Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. Cancer Res 66:7151-7
De Soto, Joseph A; Wang, Xianyan; Tominaga, Yohei et al. (2006) The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors. Int J Biol Sci 2:179-85
Smolen, Gromoslaw A; Muir, Beth; Mohapatra, Gayatry et al. (2006) Frequent met oncogene amplification in a Brca1/Trp53 mouse model of mammary tumorigenesis. Cancer Res 66:3452-5
Overholtzer, Michael; Zhang, Jianmin; Smolen, Gromoslaw A et al. (2006) Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A 103:12405-10

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