We and others have been interested in developing an animal model of BRCA1 mediated tumor suppression. Unfortunately, several groups have now reported that homozygous Brca1 knockout mice exhibit early embryonic lethality. In addition, hemizygous knockouts show no increased incidence of mammary tumors in nearly two years of follow-up. Fortunately, while mice may not represent useful models of BRCA1-related human disease, they could still serve as experimental models to address the function of BRCA1 in vivo. For example, can BRCA1 overexpression suppress mammary tumorigenesis, and if so, is this tumor suppression specific? Are there any detrimental physiologic or developmental consequences of BRCA1 overexpression? And finally, are the developmental and tumor suppressive functions of BRCA1 explicitly linked or are they in fact separate and distinct? To answer these questions we propose to generate and characterize MMTV-full length wild type BRCA1 transgenic mice. In preliminary experiments in collaboration with the laboratories of Dr. Hal Moses and Dr. Jeff Holt, we generated an MMTV- BRCA1 splice variant transgenic (BRCA1sv). This splice variant encodes amino acids 72-1863 of human BRCA1 and inhibits tumor growth in cultured cells and in vivo. It was our supposition that overexpressing BRCA1sv would lead to stunting of mammary development and suppression of tumor formation similar to the effect seen in MMTV-TGFbeta transgene mice. Paradoxically, these animals show premature development of the mammary gland. One possible explanation is that mouse embryonic stem cells are known to require Brca1 to proliferate, so enhanced expression of the human homologue may stimulate the proliferation and development of the mammary gland. We plan to test the specificity of the phenotype by generating full length and selected mutant BRCA1 transgenics. These mice will allow us to test if BRCA1 expression inhibits tumorigenesis under a variety of experimental conditions. Specifically, we will test for the ability of BRCA1 to suppress tumor formation secondary to oncogene overexpression and known carcinogens. These studies will enable us to ascertain whether the tumor suppression activity of BRCA1 is a general phenomena for all breast tumor or is limited to tumors caused by specific genetic alterations. Finally, to test the linkage of tumor suppression and development we will generate transgenic mice expressing the minimal region of BRCA1 sufficient for growth inhibition in tumor cell lines and examine them for mammary phenotypic alterations.
| Rizki, Aylin; Weaver, Valerie M; Lee, Sun-Young et al. (2008) A human breast cell model of preinvasive to invasive transition. Cancer Res 68:1378-87 |
| Campbell, Mel; Qu, Shimian; Wells, Sam et al. (2003) An adenoviral vector containing an arg-gly-asp (RGD) motif in the fiber knob enhances protein product levels from transgenes refractory to expression. Cancer Gene Ther 10:559-70 |
