) The goal of the proposed research is to evaluate a potential role for the BCL- 2 proto-oncogene, a negative regulator of apoptosis, in normal breast development and in the etiology of breast cancer. The transgenic mouse is employed as an in vivo model system. A genetic suppressor element (GSE) that has been shown to downregulate BCL-2 expression in human breast cancer cells and to sensitize these cells to apoptotic cell death will be placed under the transcriptional control of a mouse mammary gland- specific promoter and introduced as a transgene into mice. Mice that express the GSE transgene and display reduced BCL-2 expression in mammary gland will be examined for morphological and histological aberrations in mammary gland that would support a role for BCL-2 in normal breast development. To explore the potential involvement of BCL-2 in breast tumorigenesis, transgenic and nontransgenic controls will be compared following the application of a mammary carcinogenesis protocol. The two groups will be compared for differences in tumor incidence, size, number, morphology, etc., to determine whether GSE- mediated downregulation of BCL-2 in mammary tissue influences the development and/or progression of disease.
