Targeting the death machinery in mammary epithelial cells: Implications for breast cancer from transgenic and tissue culture experiments

Apoptosis plays important roles in the development of the mammary gland, and its impairment has been speculated to promote breast cancer. In mammary epithelial cells apoptosis is triggered via the intrinsic pathway which is controlled by interactions between pro- and anti-apoptotic members of the Bcl-2 protein family. The impact of impairing this pathway on the development of breast cancer has been addressed experimentally using transgenic mouse models. Neither overexpression of anti-apoptotic Bcl-2 nor a deficiency of pro-apoptotic Bax were tumorigenic on their own in mammary glands of transgenic mice. Both ways of impairing apoptosis, however, promoted mammary tumorigenesis elicited by c-myc or SV40 T antigen. Likewise, inhibition of the intrinsic pathway in a three-dimensional mammary tissue culture model was insufficient to generate solid aggregates resembling early breast cancer stages but required the concomitant activity of proliferation-stimulating oncogenes. These two experimental approaches have thus substantiated the concept of apoptosis acting as a tumor suppressor mechanism, however point towards a complex picture in which alternative routes to cell death may be involved.