Kang K S, Sun W, Nomata K, Morita I, Cruz A, Liu C J, Trosko J E, Chang C C
Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing 48824-1317, USA.
Mol Carcinog. 1998 Apr;21(4):225-33.
Ionizing radiation is the exogenous agent best proven to induce breast cancer. c-erbB2/neu amplification and overexpression are known to occur in breast cancer and are correlated with aggressive tumor growth and poor prognosis. We have developed simian virus 40-immortalized cell lines from normal human breast epithelial cells (HBECs) with luminal and stem-cell characteristics. In this study, we examined whether x-rays and a mutated neu oncogene are capable of inducing tumorigenicity in these cells. The results indicated that x-rays were effective in converting immortal non-tumorigenic HBECs to weakly tumorigenic cells that then could be transformed to highly tumorigenic cells by the neu oncogene. The in vitro growth of these tumorigenic cells was significantly faster than that of the parental non-tumorigenic cells in growth factor- and hormone-supplemented or -depleted media. The neu oncogene, however, had no tumorigenic effect on immortal non-tumorigenic cells. The expression of p185(c-erb82/neu) was elevated in neu-transduced immortal or weakly tumorigenic cell lines. However, only in the latter was p185(c-erbB2/neu) found to be phosphorylated at tyrosine residues. Thus, x-rays appear to induce a genetic alteration that confers weak tumorigenicity on immortal HBECs and interacts with p185(c-erbB2/neu) directly or indirectly to give rise to fast-growing tumors.
电离辐射是已被充分证实可诱发乳腺癌的外源性因素。已知c-erbB2/neu基因扩增和过表达在乳腺癌中出现，并与肿瘤的侵袭性生长和不良预后相关。我们已从具有管腔和干细胞特征的正常人乳腺上皮细胞（HBECs）中建立了猿猴病毒40永生化细胞系。在本研究中，我们检测了X射线和突变的neu癌基因是否能够在这些细胞中诱发肿瘤形成能力。结果表明，X射线可有效地将永生化的非致瘤性HBECs转化为弱致瘤性细胞，然后这些细胞可通过neu癌基因转化为高致瘤性细胞。在添加或去除生长因子和激素的培养基中，这些致瘤性细胞的体外生长速度明显快于亲代非致瘤性细胞。然而，neu癌基因对永生化的非致瘤性细胞没有致瘤作用。在转导neu基因的永生化或弱致瘤性细胞系中，p185（c-erb82/neu）的表达升高。然而，仅在后一种细胞系中发现p185（c-erbB2/neu）在酪氨酸残基处被磷酸化。因此，X射线似乎诱导了一种基因改变，赋予永生化HBECs弱致瘤性，并直接或间接与p185（c-erbB2/neu）相互作用，从而产生快速生长的肿瘤。
