期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：5
页码：1257-1262
DOI：10.1073/pnas.0308090100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：MCF10A mammary epithelial cells form growth-arrested structures when cultured in three-dimensional basement membrane gels. Activation of the receptor tyrosine kinase ErbB2 induces formation of proliferative structures that share properties with noninvasive early stage lesions. We conducted a genetic screen to identify cDNAs that can cooperate with ErbB2 to induce migration in these cells, with the hypothesis that they would represent candidate "second hits" in the development of invasive breast carcinomas. We found that expression of transforming growth factor (TGF){beta}1 and TGF{beta}3 in cells expressing activated ErbB2 induces migration in transwell chambers and invasive behavior in both basement membrane cultures and invasion chambers. The ability of ErbB2 to cooperate with TGF{beta} correlated with sustained, elevated activation of extracellular signal-regulated kinase (Erk)-mitogen-activated protein kinase. Pharmacological reduction of Erk activity inhibited the cooperative effect of TGF{beta} and ErbB2 on migration and expression of activated Erk kinase was sufficient to cooperate with TGF{beta} to induce migration and invasion, suggesting that sustained Erk activation is critical for ErbB2/TGF{beta} cooperation. In addition, we show that costimulation of ErbB2 and TGF{beta} induces autocrine secretion of factors that are sufficient to induce migration, but not invasion, by means of both epidermal growth factor receptor-dependent and -independent processes. These results support the role of TGF{beta} as a pro-invasion factor in the progression of breast cancers with activated ErbB2 and suggest that activation of the Erk and epidermal growth factor receptor pathways are key in mediating these events.
