BREAST-CARCINOMA - A COLLECTIVE DISORDER

The development and differentiation of the epithelial component of gla ndular tissues such as the breast is regulated by two apparently unrel ated processes. One of these is presumed to be epithelial cell collect ive autonomous, that is, it is mediated by gene products which act dir ectly on the epithelial cells. An important component of autonomous re gulation is the functional expression of homotypic cell-cell adhesion molecules such as cadherins. The second process is non-autonomous and involves an inductive effect of the neighboring mesenchymal cell colle ctive. An important component of non-autonomous regulation is the aggr egation/condensation of mesenchyme closely associated with the epithel ium. We propose that molecular alterations in autonomous and non-auton omous pathways are important causes and indicators respectively of bre ast cancer progression and that these two fundamental regulators of ep ithelial collective organization are in fact inter-dependent. For exam ple, we show that the expression of hepatocyte growth factor (HGF), an epithelially targeted mesenchymally derived morphogenic factor is reg ulated by mesenchymal cell density (condensation) and by factors relea sed from epithelial cells. Breast epithelial cells produce factors whi ch inhibit and stimulate HGF expression. The inhibitory factor is tran sforming growth factor beta (TGF-beta) and the activation state of TGF -beta is a crucial element in HGF homeostasis. The balance of negative and positive HGF regulators is markedly affected by the growth condit ions and differentiation state of the epithelial cells. The expression of the HGF receptor, met, is high in normal breast epithelial cells a nd in dedifferentiated (ER negative) tumor cells but is reduced or los t in ER positive well differentiated epithelial cells. Our results ind icate that the expression of at least one epithelial morphogen, HGF, i s inter-dependently regulated by mesenchymal condensation and by facto rs released by neighboring epithelial cells.