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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cooperation of the ErbB2 receptor and transforming growth factor β in induction of migration and invasion in mammary epithelial cells
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Cooperation of the ErbB2 receptor and transforming growth factor β in induction of migration and invasion in mammary epithelial cells

机译：ErbB2受体和转化生长因子β在诱导乳腺上皮细胞迁移和侵袭中的协同作用

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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)/β1 and TGFβ3 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 TGFβ correlated with sustained, elevated activation of extracellular signal-regulated kinase (Erk)-mitogen-acti-vated protein kinase. Pharmacological reduction of Erk activity inhibited the cooperative effect of TGF? and ErbB2 on migration and expression of activated Erk kinase was sufficient to cooperate with TGFβ to induce migration and invasion, suggesting that sustained Erk activation is critical for ErbB2/TGFβ cooperation. In addition, we show that costimulation of ErbB2 and TGFβ 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 TGFβ 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.
机译：当在三维基底膜凝胶中培养时，MCF10A乳腺上皮细胞会形成生长受阻的结构。受体酪氨酸激酶ErbB2的激活诱导与非侵入性早期病变共享特性的增殖结构的形成。我们进行了一次遗传筛选，以鉴定可以与ErbB2协同作用以诱导这些细胞迁移的cDNA，并假设它们将代表浸润性乳腺癌发展中的候选“第二击”。我们发现，在表达活化的ErbB2的细胞中表达转化生长因子（TGF）/β1和TGFβ3诱导了跨孔室的迁移以及在基底膜培养和侵袭室中的侵袭行为。 ErbB2与TGFβ协同作用的能力与细胞外信号调节激酶（Erk）-丝裂原活化的蛋白激酶的持续升高激活有关。降低Erk活性的药理作用抑制了TGFβ？ ErbB2和ErbB2对活化的Erk激酶的迁移和表达足以与TGFβ协同诱导迁移和侵袭，这表明持续的Erk活化对于ErbB2 /TGFβ的协同作用至关重要。另外，我们表明，通过表皮生长因子受体依赖性和非依赖性过程，ErbB2和TGFβ的共刺激诱导自分泌分泌足以诱导迁移但不入侵的因子的自分泌。这些结果支持了TGFβ作为激活的因子在具有激活的ErbB2的乳腺癌进展中的作用，并且表明Erk和表皮生长因子受体途径的激活是介导这些事件的关键。

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