INVOLVEMENT OF TYROSINE PHOSPHORYLATION OF P185(C-ERBB2 NEU) IN TUMORIGENICITY INDUCED BY X-RAYS AND THE NEU ONCOGENE IN HUMAN BREAST EPITHELIAL-CELLS/

Ionizing radiation is the exogenous agent best proven to induce breast cancer. c-erbB2/neu amplification and overexpression are known to occ ur in breast cancer and are correlated with aggressive tumor growth an d poor prognosis. We have developed simian virus 40-immortalized cell lines from normal human breast epithelial cells (HBECs) with luminal a nd stem-cell characteristics. In this study, we examined whether x-ray s and a mutated neu oncogene are capable of inducing tumorigenicity in these cells. The results indicated that x-rays were effective in conv erting immortal non-tumorigenic HBECs to weakly tumorigenic cells that then could be transformed to highly tumorigenic cells by the neu onco gene. The in vitro growth of these tumorigenic cells was significantly faster than that of the parental non-tumorigenic cells in growth fact or-and hormone-supplemented or -depleted media. The neu oncogene, howe ver, had no tumorigenic effect on immortal non-tumorigenic cells. The expression of p185(c-erbB2/neu) was elevated in neu-transduced immorta l or weakly tumorigenic cell lines. However, only in the latter was p1 85(c-erbB2/neu) found to be phosphorylated at tyrosine residues. Thus, x-rays appear to induce a genetic alteration that confers weak tumori genicity on immortal HBECs and interacts with p185(c-erbB2/neu) direct ly or indirectly to give rise to fast-growing tumors. (C) 1998 Wiley-L iss, Inc.