The objectives of this revised new application are to continue development and study of a mouse model system which may provide insight into three aspects of breast cancer. Specifically, the applicant will utilize the recently developed transgenic mammary gland approach in studies of the divergent roles of the two most prevalent EGF family members in breast cancer: transforming growth factor alpha (TGFa) and amphiregulin (AR). He will examine in detail the contrasting effects of these two growth factors on mammary epithelial apoptosis, immortalization, tumorigenesis, and genetic instability. In addition, the interaction of each growth factor will be examined with the myc oncogene. Myc is an oncogene which promotes tumorigenesis by synergistic interaction with survival-promoting growth factors. Amplification of myc has been associated with poor prognosis of breast cancer in postmenopausal women. The purpose of the application will be to first characterize effects of AR and TGFa on the Bcl-XL/Bax ratio to modulate epithelial apoptosis, on telomerase to prevent epithelial senescence, and on cyclin D1/cdk-4 to shorten the G1 phase of the cell cycle. Genetic instability will be studied with a series of techniques, including newly established spectral karyotyping and comparative genomic hybridization methods. Subsequent aims compare AR and TGFa for effects on mammary stem cells, and for interaction with the Bcl-XL and Bcl-SS genes and the Myc oncogene using a combined transgenic mammary gland - transgenic mouse approach. This application is expected to provide insight into differential mechanisms of two EGF family growth factors to induce hyperplasia, interact with pregnancy/lactation, and interact with an oncogene particularly relevant to postmenopausal breast cancer.
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