Multiple cell-intrinsic genetic changes have been associated with the transformation of normal to neoplastic cells, yet cancer remains a disease only in the context of the entire organism. Thus, the behavior of neoplastic cells in vivo is inextricably linked to the tumor microenvironment. However, because-of the variety of cell types and the complex array of tissue-and organ-specific homeostatic mechanisms affecting cells, the relationship between tumors and their environment has been difficult to assess. The studies outlined in this proposal are directed at establishing methodologies whereby genotypically distinct cell populations within a single organ, the mammary gland, can be uniquely marked so as to permit analysis of their interactions during preneoplasia, and neoplasia. Specifically, the studies involve two genotypes associated with enhanced mammary carcinogenesis, the Min mouse, which carries a point mutation in the murine homolog of the human adenomatous polyposis coli gene, and transgenic mice with mammary epithelial targeted expression of transforming growth factor alpha (TGF-alpha). In the Min mouse, enhanced tumor susceptibility is associated with the apparent loss of one functional allele. In TGF-alpha transgenic mice, tumorigenesis results from growth factor overexpression. Chimeric mice will be generated hearing combinations of these and wild-type genotypes, and the character of cellular interactions will be assessed at the boundaries between different somatic genotypes. Issues addressed include tumor clonality, the cellular autonomy of Min and TGF-alpha activities, TGF-alpha/Min interactions, and the significance of a stromal versus epithelial site of activity of either genotype. The goal of these experiments is to identify, within the microenvironmental context, the modes of action of mechanistically diverse tumorigenic genetic changes.
