Molecular Analysis of Bcl-xs-Induced Apoptosis in Breast Cancer.

A major genetic event that occurs in the pathogenesis of breast carcinoma involves alterations in the Bcl-2 survival pathway. To determine the role of the Bcl-2 family in maintaining cancer cell viability, we constructed a recombinant adenovirus vector that expresses Bcl-xs, a dominant inhibitor of these proteins. Even in the absence of an exogenous apoptotic signal, this recombinant virus specifically and efficiently activates apoptosis in human carcinoma cells including those from breast. In the original proposal, we proposed studies to determine the mechanism involved in Bcl-xs-mediated apoptosis, to characterize cellular proteins that interact with Bcl-xs using biochemical and genetic approaches, and to use a transgenic model of Bcl-xs expression in the breast to assess the requirement for Bcl-2Bcl-xs in the maintenance of normal breast epithelia and tumor growth. During the last year, we have characterized the interaction of Bcl-xs with Bcl-2 and Bcl-xs and identified through a genetic screen, HRK, a novel protein that interacts with Bcl-2 and Bcl-xs. Finally, transgenic mice expressing Bcl-xs in the breast have been developed and partially characterized.