Growth Factors, Apoptosis, and Survival of Mammary Epithelial Cells

Programmed cell death (apoptosis) occursregularly during normal growth and development of themammary gland. One of the most dramatic examples ofapoptosis is evident during the remodeling of the breast that accompanies postlactational involution.Transgenic mouse models have demonstrated thatoverexpression of polypeptides such as transforminggrowth factor alpha (TGFα)3 and insulinlike growth factor I (IGF-I) can block this remodeling, suggestingthat these growth factors may be acting as survivalfactors for the mammary epithelium. In contrast,transgenic mice that overexpress the growth inhibitor transforming growth factor beta (TGF-β)show increased apoptosis in the mammary epitheliumthroughout mammary development, suggestive of amechanism working to counterbalance the survivalfactors. Experiments with mammary epithelial cell lines cultured invitro have confirmed that these growth factors canindeed regulate apoptosis and survival in mammaryepithelial cells; EGF, IGF-I, and basic fibroblastgrowth factor (bFGF) act as survival factors formammary epithelial cells, while TGF-β induces theirdeath. In breast cancer, cytotoxic drugs and hormoneablation increase the expression of TGF-β, which may function to induce cell death by eitherparacrine or autocrine mechanisms. Lastly, although ithas very limited expression in the breast, TNFαhas been shown to be effective in the rapid, direct induction of cell death in breast cancer celllines. Together, these studies describe a complexdynamic pattern of cell death-inducing and survivalfactors that promote the development of the maturemammary gland and that rapidly remodel the tissue afterlactation.