INCREASED EXPRESSION OF C-ERBB-2 IN HORMONE-DEPENDENT BREAST-CANCER CELLS INHIBITS CELL-GROWTH AND INDUCES DIFFERENTIATION

c-erbB-2, a member of the tyrosine kinase oncogene family, is overexpr essed in about 30% of human breast tumors where it correlates with poo r prognosis. In vitro studies have suggested that increased expression of the receptor plays an important role in malignant progression. To better understand the direct effects of p185(HER2) overexpression, a h uman c-erbB-2 expression vector was transfected into the hormone-depen dent MCF-7 human breast carcinoma cell line and cell growth was analys ed. Unexpectedly, colony formation assay revealed a reduction in the n umber and size of colonies as compared with mock-transfected cells. In hormone-deprived medium, c-erbB-2 transfected cells acquired growth c apability, consistent with previous reports. By contrast, two c-erbB-2 -transfected clones grown in complete medium showed a reduced prolifer ation rate despite the activation of a fully functional oncoprotein ca pable of autophosphorylation and induction of the MAPK pathway. The nu mber of c-erbB-2-overexpressing cells in the S phase of the cell cycle was about one-half the number of control and mock-transfected cells. Also, overexpression of c-erbB-2 induced overexpression of p21(WAF1), pRB hypophosphorylation and a mature differentiated cell phenotype wit h production of lipid droplets. Functional inactivation of p185(HER2) by means of a specific single chain antibody indicated the c-erbB-2-de pendence of the observed alterations. These data show that the exogeno us overexpression of the c-erbB-2 gene in hormone-dependent breast can cer cells inhibits proliferation and induces differentiation.