Cooperation of the ErbB2 receptor and transforming growth factor β in induction of migration and invasion in mammary epithelial cells
Cooperation of the ErbB2 receptor and transforming growth factor β in induction of migration and invasion in mammary epithelial cells
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DOI：
10.1073/pnas.0308090100
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发表时间：
2004-02-03
影响因子：
11.1
通讯作者：
Brugge, JS
中科院分区：
文献类型：
--
作者：
Seton-Rogers, SE;Lu, Y;Brugge, JS
MCF 10A乳腺上皮细胞在三维基底膜凝胶中培养时形成生长停滞结构。受体酪氨酸激酶ErbB 2的激活诱导与非侵入性早期病变具有相同性质的增殖结构的形成。我们进行了遗传筛选，以确定可以与ErbB 2合作，以诱导这些细胞中的迁移的cDNA，假设他们将代表候选人的“二次打击”在浸润性乳腺癌的发展。我们发现，表达转化生长因子（TGF）β 1和TGF β 3的细胞表达活化ErbB 2诱导迁移transwell室和侵袭行为在基底膜培养和侵袭室。Erb β 2与TGF β合作的能力与细胞外信号调节激酶（Erk）-促分裂原活化蛋白激酶的持续、升高的活化相关。Erk活性的药理学降低抑制了TGF β和ErbB 2对迁移的协同作用，并且活化的Erk激酶的表达足以与TGF β协同诱导迁移和侵袭，这表明持续的Erk活化对于ErbB 2/TGF β协同作用至关重要。此外，我们表明，ErbB 2和TGF β共刺激诱导自分泌的因子，足以诱导迁移，但不入侵，通过表皮生长因子受体依赖和独立的过程。这些结果支持TGF β作为促侵袭因子在具有活化ErbB 2的乳腺癌进展中的作用，并表明Erk和表皮生长因子受体途径的活化是介导这些事件的关键。
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)beta1 and TGFbeta3 in cells expressing activated ErbB2 induces migration in transwell chambers and invasive behavior in both basement membrane cultures and invasion chambers. The ability of Erbbeta2 to cooperate with TGFbeta 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 TGFbeta and ErbB2 on migration and expression of activated Erk kinase was sufficient to cooperate with TGFbeta to induce migration and invasion, suggesting that sustained Erk activation is critical for ErbB2/TGFbeta cooperation. In addition, we show that costimulation of ErbB2 and TGFbeta 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 TGFbeta 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.