Growth factors and their receptors in neoplastic mammary glands

Control of the growth of mammary glands is largely exerted in vivo by systemic hormones and locally-produced growth factors, whereas malignant tumours gradually lose the ability to respond to both types of control in vivo. However, the systemic hormones have little direct effect on stimulating the growth of rat or human mammary cell lines in vitro. Estrogens are thought to work by stimulating locally-produced growth factors and/or their receptors, eg transferrin, TGF alpha and IGF-1, and prolactin by a contaminating pituitary mammary growth factor (PMGF). Mammary stem cells intermediate between epithelial and myoepithelial cells are thought to be retained in malignant carcinomas, whereas the TGF alpha and bFGF-producing myoepithelial cells are lost. Hormonal autonomy of carcinomas may develop by overproduction of the locally-produced growth factors, their receptors (including related receptors, eg c-erbB-2) and/or by stem cells differentiating sufficiently to utilise normal control mechanisms, eg refractivity to PMGF and autocrine/paracrine response to bFGF. The failure of the stem cells to differentiate completely to myoepithelial cells in carcinomas greatly reduces the heparan sulphate proteoglycan sink used to sequester to bFGF in normal glands and also removes the possibility of eliminating cells by terminal differentiation, both processes possibly contributing to the uncontrolled growth of the malignant breast cell.