Growth and differentiation of the normal mammary gland and its tumours.

The mammary glands of non-pregnant rodents and humans consist of epithelial, intermediate stem and myoepithelial cells, and these have been isolated as cell lines in vitro. Growth factors produced by the myoepithelial cells, e.g. transforming growth factor alpha (TGF alpha) and basic fibroblast growth factor (bFGF), can stimulate the growth of the intermediate stem cells in vitro. One protein, p9Ka, a calcium binding regulatory protein, arises at an early stage of the differentiation of epithelial into myoepithelial cells in vitro and is associated with the cytoskeleton; another, cathepsin D, is a protease associated with this pathway in vivo. Unlike normal glands and benign lesions, malignant mammary carcinomas of rats and humans do not contain fully differentiated myoepithelial cells, and the resultant cell lines fail to differentiate completely into myoepithelial cells. Loss of the myoepithelial cells in some human invasive carcinomas may account, in part, for compensatory changes in the malignant cells. For example, overexpression of TGF alpha/ErbB-2 receptors may compensate for a decrease in TGF alpha, whereas ectopic production of bFGF and its receptors, and of p9Ka and cathepsin D, may help in tumorigenesis and in metastasis respectively. Thus compensation for, or retention of, molecules potentially involved in growth and/or differentiation by some human invasive carcinomas may be a mechanism by which a malignancy progresses.