Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model

Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast, Gain of Bcl-2 function i n mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial c ell survival and proliferation at three key stages in oncogenesis: the init ial proliferative process, hyperplasia, and cancer. During the initial prol iferative process, Bcl-2 strongly inhibited both apoptosis and mitotic acti vity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma , the inhibitory effects on mitotic activity were lost. In contrast, anti-a poptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In thi s model, retention of anti-apoptotic activity with loss of anti-proliferati ve action resulted in earlier tumor presentation.