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. We have performed 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-XL in the maintenance of normal breast epithelia and tumor growth. The analysis showed that Bcl-xS requires its BH3 and C-terminal mitochondrial anchoring domains for killing. Bcl-XS-induced killing is, at least in part, mediated through an Apaf-l-caspase-9 pathway. Bcl-xS associates with Bcl-xL via its BH3 domain and with Apaf-l possibly through Bcl-xL. We have cloned and characterized several Apaf-l cDNAs and showed that a novel Apaf-l isoform activates procaspase-9 in a cytochrome c and dATP-dependent manner. Finally, transgenic mice expressing Bcl-XS in the breast have been generated. Female Bcl-XS mice showed dysmption of mammary hyperplasia and differentiation associated with pregnancy.