Relationship of growth factors and differentiation in normal and neoplastic development of the mammary gland.

The different mammary cell lines described herein appear to be representative of the cell types found in both normal glands and benign tumors of rats and humans. The epithelial cell lines can differentiate to both alveolar-like and myoepithelial-like cells in culture. The epithelial cell lines and particularly those cell lines representing intermediate stages in the myoepithelial differentiation pathway are candidates for the epithelial stem cells found in rat and possibly in human terminal ductal structures. The systemic mammatrophic hormones that are thought to control the growth of the mammary gland in vivo have little or no stimulatory effect alone on the growth of normal and neoplastic rat mammary cells in culture. The pituitary growth factors (fibroblast growth factor [FGF] and pituitary-derived mammary growth factor [PMGF],) and the growth factors released from the different cell lines, (stromal prostaglandin E2 [PGE2] and myoepithelial transforming growth factor alpha [TGF-alpha]) are much more potent mitogenic agents for the mammary cell lines. The ability of FGF and epidermal growth factor (EGF) -related molecules to simulate growth of the different mammary cell types in culture correlates with the presence of their high-affinity receptors. Thus these growth factors are promising candidates for some of the primary effectors of mammary growth in vivo. Malignant mammary epithelial cells have a greatly reduced rate of growth compared to their normal and benign counterparts. They also fail to differentiate or to respond to PMGF but can still respond to PGE2 and TGF-alpha. In addition, highly malignant variants appear capable of adapting to a new growth environment in vivo. This suggests that simple molecular explanations based solely on the autostimulation of cell growth may not be sufficient to explain some of the properties of the slowly growing, highly malignant cells.