Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

Abstract

c-erbB-2, a member of the tyrosine kinase oncogene family, is overexpressed in about 30% of human breast tumors where it correlates with poor prognosis. In vitro studies have suggested that increased expression of the receptor plays an important role in malignant progression. To better understand the direct e ects of p185 HER2 overexpression, a human c-erbB-2 expression vector was transfected into the hormone-dependent MCF-7 human breast carcinoma cell line and cell growth was analysed. Unexpectedly, colony formation assay revealed a reduction in the number and size of colonies as compared with mock-transfected cells. In hormone-deprived medium, c-erbB-2 transfected cells acquired growth capability, consistent with previous reports. By contrast, two c-erbB-2-transfected clones grown in complete medium showed a reduced proliferation rate despite the activation of a fully functional oncoprotein capable of autophosphorylation and induction of the MAPK pathway. The number 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 di erentiated cell phenotype with production of lipid droplets. Functional inactivation of p185 HER2 by means of a speci®c single chain antibody indicated the c-erbB-2-dependence of the observed alterations. These data show that the exogenous overexpression of the c-erbB-2 gene in hormonedependent breast cancer cells inhibits proliferation and induces di erentiation.

Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

“…First, RPTPa-induced Src activation may exert di erent e ects in di erent settings or cellular contexts. Analogously, HER2/neu is tumorigenic in 3T3 ®bro-blasts (Di Fiore et al, 1987), yet when overexpressed in MCF7 breast carcinoma cells leads to growth inhibition and di erentiation (Giani et al, 1998). One mechanism through which Src family kinases have been linked to negative growth regulation is phosphorylation of the Cbl protein, leading to degradation of PDGFR-a (Rosenkranz et al, 2000).…”

Biologic and therapeutic role of HER2 in cancer

“…Nevertheless, HER2 signaling is carefully regulated in cells and excess signaling induces apoptosis in cells carrying a wild-type p53 gene (Peles et al, 1992;Daly et al, 1997Daly et al, , 1999Giani et al, 1998). This observation implies the presence of other alterations related to the apoptotic pathway in tumor cells that allow the shift from apoptosis to proliferation and survival in the face of HER2 oversignaling (Casalini et al, 2001;Huang et al, 2002).…”

p185neu protein is required for tumor and anchorage-independent growth, not for cell proliferation of transgenic mammary carcinoma

“…In human prepartum and lactating mammary specimens, p185 HER-2 expression was detected at an intensity comparable to that of breast carcinomas (Kacinski et al, 1995). In another study, transfection of HER-2 gene into MCF-7 breast carcinoma cells appeared to increase differentiation of these cells (Giani et al, 1998). The pattern of tumor growth of p185 neu -negative cells, observed in our study, i.e., a long latency period followed by the emergence of a fast-growing variant, is reminiscent of the behavior of dormant tumors (Demicheli et al, 1994).…”