Growth factors, apoptosis, and survival of mammary epithelial cells

Programmed cell death (apoptosis) occurs regularly during normal growth and development of the mammary gland. One of the most dramatic examples of apo ptosis is evident during the remodeling of the breast that accompanies post lactational involution. Transgenic mouse models have demonstrated that over expression of polypeptides such as transforming growth factor cw (TGF alpha )(3) and insulin like growth factor I(IGF-I) can block this remodeling, sug gesting that these growth factors may be acting as survival factors for the mammary epithelium. In contrast, transgenic mice that overexpress the grow th inhibitor transforming growth factor beta (TGF-beta) show increased apop tosis in the mammary epithelium throughout mammary development, suggestive of a mechanism working to counterbalance the survival factors. Experiments with mammary epithelial cell lines cultured in vitro have confirmed that th ese growth factors can indeed regulate apoptosis and survival in mammary ep ithelial cells; EGF, IGF-I, and basic fibroblast growth factor (bFGF) act a s survival factors for mammary epithelial cells, while TGF-beta induces the ir death. In breast cancer, cytotoxic drugs and hormone ablation increase t he expression of TGF-beta, which may function to induce cell death by eithe r paracrine or autocrine mechanisms. Lastly, although it has very limited e xpression in the breast, TNF alpha has been shown to be effective in the ra pid, direct induction of cell death in breast cancer cell lines. Together, these studies describe st complex dynamic pattern of cell death-inducing an d survival factors that promote the development of the mature mammary gland and that rapidly remodel the tissue after lactation.