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 apoptosis is evident during the remodeling of the breast that accompanies postlactational involution. Transgenic mouse models have demonstrated that overexpression of polypeptides such as transforming growth factor alpha (TGFalpha) and insulin like growth factor I (IGF-I) can block this remodeling, suggesting that these growth factors may be acting as survival factors for the mammary epithelium. In contrast, transgenic mice that overexpress the growth inhibitor transforming growth factor beta (TGF-beta) show increased apoptosis 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 these growth factors can indeed regulate apoptosis and survival in mammary epithelial cells; EGF, IGF-I, and basic fibroblast growth factor (bFGF) act as survival factors for mammary epithelial cells, while TGF-beta induces their death. In breast cancer, cytotoxic drugs and hormone ablation increase the expression of TGF-beta, which may function to induce cell death by either paracrine or autocrine mechanisms. Lastly, although it has very limited expression in the breast, TNFalpha has been shown to be effective in the rapid, direct induction of cell death in breast cancer cell lines. Together, these studies describe a complex dynamic pattern of cell death-inducing and survival factors that promote the development of the mature mammary gland and that rapidly remodel the tissue after lactation.