Breast cancer is a complex disease that is influenced by multiple factors. The long-range goal of this project is to understand the role of the retrovirus, mouse mammary tumor virus (MMTV), in murine mammary tumorigenesis, alone and in combination with chemical carcinogens. The general approach attempts to relate events at the molecular level with the biological features of breast cancer in the BALB/c mouse model system. The immediate goals addressed in this proposal are designed to distinguish among possible molecular mechanisms of MMTV oncogenicity and establish virus involvement, if any, in mammary carcinogenesis induced by chemicals. Our working hypothesis is that the product of the MMTV long terminal repeat (LTR) gene has cellular immortalizing properties and that a mammary epithelial cell-specific oncogene is involved in complete mammary cell transformation.
Specific aims are the following: (1) To monitor cellular oncogene and MMTV gene expression during normal mammary gland development and in defined stages in mammary carcinogenesis, including preneoplastic tissue, (2) To determine whether the chemical carcinogen, DMBA, activates cellular oncogene or MMTV gene expression in the mouse mammary gland, either prior to tumor appearance or in the resultant tumors (studies will include transfection experiments using established mammary epithelial cell lines to detect mammary-specific oncogenes), (3) To detect and characterize putative transforming proteins, including the MMTV LTR gene product and int region products, and determine their possible relevance to mammary tumorigenesis, and (4) To recover phenotypically altered epithelial cells from mouse mammary glands during the latent period before tumor appearance. A major strength of the BALB/c mouse model system is that the studies will be well internally controlled, allowing observations of gene expression to be interpreted in proper perspective. Gene expression will be compared during normal gland development, in preneoplastic tissue (the intermediate stage in mammary tumorigenesis), and in tumors induced by chemical carcinogen. This project should yield insights into molecular and cellular mechanisms important in breast cancer causation.
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