Shen K, Novak R F
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Biochem Biophys Res Commun. 1997 Feb 3;231(1):17-21. doi: 10.1006/bbrc.1996.6039.
Several environmental organochlorines, some of which exhibit estrogenic activity, have been detected in human breast tissue and have been suggested as having a role in tumorigenesis. In this communication, we report the effects of DDT on c-erbB2 and c-met growth factor receptor tyrosine kinase and STATS signal transduction processes in human breast epithelial MCF-10A cells. p,p'-DDT at physiologically relevant concentrations (i.e. 10 nM) elevated c-erbB2, c-met and STAT1 alpha (p84/91) tyrosine phosphorylation, stimulated Grb2-Sos1 association and elevated MAPK phosphorylation. In contrast, o,p'-DDT under identical conditions failed to stimulate either c-erbB2 or c-met tyrosine phosphorylation, demonstrating a structural specificity for this effect. p,p'-DDT also stimulated breast epithelial cell proliferation, as evidenced by 3H thymidine incorporation and analysis of cell doubling times. These results provide evidence of additional pathways by which environmental chemicals may stimulate cell proliferation and/or tumorigenesis and thereby function as xenomitogens.
在人体乳腺组织中已检测到几种环境有机氯，其中一些具有雌激素活性，并被认为在肿瘤发生中起作用。在本报告中，我们报道了滴滴涕（DDT）对人乳腺上皮MCF-10A细胞中c-erbB2和c-met生长因子受体酪氨酸激酶以及信号转导和转录激活因子（STAT）信号转导过程的影响。生理相关浓度（即10 nM）的p,p'-滴滴涕可提高c-erbB2、c-met和STAT1α（p84/91）的酪氨酸磷酸化水平，刺激生长因子受体结合蛋白2（Grb2）-七号染色体失活蛋白1（Sos1）结合，并提高丝裂原活化蛋白激酶（MAPK）的磷酸化水平。相比之下，在相同条件下，o,p'-滴滴涕未能刺激c-erbB2或c-met的酪氨酸磷酸化，表明这种效应具有结构特异性。p,p'-滴滴涕还可刺激乳腺上皮细胞增殖，这可通过3H胸苷掺入及细胞倍增时间分析得到证实。这些结果为环境化学物质刺激细胞增殖和/或肿瘤发生并因此作为外源性有丝分裂原发挥作用的其他途径提供了证据。
