The overall goal of this application is to address the genetic and hormonal mechanisms underlying mammary carcinogenesis in transgenic animal models using two genes that activate distinct signal transduction pathways, transforming growth factor alpha (TGFa) and c-myc. Transgenic mice carrying either transgene develop mammary neoplasia, yet the mechanisms of tumor progression in these models appear to differ. Thus, the first aim of this proposal is to identify and explore mechanisms of preneoplasia in WAP-TGFa and WAP-c-myc transgenic mice. Second, tremendous amount of data suggests a relationship between breast cancer progression and ovarian hormones, yet the precise mechanistic character of that relationship and the way that it changes for tumors induced by different initiating stimuli remains obscure. An important advance would be provided by the establishment of animal models of mammary cancer with defined genetic cause in which the hormonal milieu could be varied without directly influencing the tumor-initiating genetic stimulus. Therefore, the second aim of this proposal is to accomplish this advance in transgenic models by targeting transgene expression to mammary epithelium using gene regulatory elements that are not hormonally responsive. This research training in molecular and cancer biology builds on the candidate's previous training in veterinary medicine (D.V.M.) and reproductive physiology (M.S., Ph.D.). This program will be carried out at an outstanding scientific institution, the University of Wisconsin- Madison. The co-sponsors, Dr. Michael Gould in the Department of Human Oncology and Dr. Eric Sandgren in the Department of Pathobiological Sciences, are highly qualified in their respective areas of breast cancer biology and transgenic models of disease. The research training program devised by the candidate and the co-sponsors and the excellent resources available ensure a productive training period that will prepare the candidate to be a well-qualified, independent biomedical researcher.
