Controlled activation of ErbB1/ErbB2 heterodimers promote invasion of three-dimensional organized epithelia in an ErbB1-dependent manner: implications for progression of ErbB2-overexpressing tumors.
Controlled activation of ErbB1/ErbB2 heterodimers promote invasion of three-dimensional organized epithelia in an ErbB1-dependent manner: implications for progression of ErbB2-overexpressing tumors.
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ErbB1/ErbB2 异二聚体的受控激活以 ErbB1 依赖性方式促进三维组织上皮细胞的侵袭：对 ErbB2 过表达肿瘤进展的影响。
DOI：
10.1158/0008-5472.can-05-4081
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发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
Muthuswamy,SenthilK
中科院分区：
文献类型：
--
作者：
Zhan,Lixing;Xiang,Bin;Muthuswamy,SenthilK
ErbB家族的受体酪氨酸激酶与包括乳腺癌在内的许多癌症有关。ErbB受体被配体诱导形成的同二聚体和异二聚体激活。受体异二聚化被认为在乳腺癌过度表达ErbB家族多个成员中起关键作用。虽然ErbB受体的共表达与患者预后不良有关，但受体异二聚体调节肿瘤进展的机制尚不清楚，部分原因是缺乏允许在乳腺上皮细胞中控制特异性受体异二聚体激活的方法。在这里，我们报告了一种在非致瘤性乳腺上皮细胞系MCF-10A中激活ErbB1-ErbB2异源二聚体的方法，而不受内源性ErbB受体的干扰。使用这种方法，我们发现ErbB2同型二聚体和ErbB1-ErbB2异源二聚体在激活Ras/丝裂原激活的蛋白激酶途径方面同样有效，而异源二聚体在激活磷酸肌肽3激酶（PI3K）和磷脂酶Cγ1途径方面比ErbB2同型二聚体更有效。我们将二聚化系统与三维细胞培养方法相结合，结果表明，ErbB2同型二聚体和ErbB1-ErbB2异源二聚体都会诱导三维腺泡样结构的破坏，而只有异源二聚体通过细胞外基质促进细胞入侵。异源二聚体诱导入侵的能力需要ErbB1激酶活性和PI3K、Ras/丝裂原活化蛋白激酶和磷脂酶Cγ1信号通路的激活。因此，我们已经确定细胞侵袭是一种异源二聚体特异性的生物学结果，并表明ErbB1的共表达可能对erbb2阳性乳腺癌的侵袭性进展起关键调节作用。（癌症研究，2006;66(10):5201-8）
Receptor tyrosine kinases of the ErbB family are implicated in a number of cancers, including that of the breast. ErbB receptors are activated by ligand-induced formation of homodimers and heterodimers. Receptor heterodimerization is thought to play a critical role in breast cancers overexpressing multiple members of the ErbB family. Although coexpression of ErbB receptors is associated with poor patient prognosis, the mechanisms by which receptor heterodimerization regulates tumor progression are not clear, due in part to a lack of methods that allow controlled activation of specific receptor heterodimers in mammary epithelial cells. Here, we report an approach to activate ErbB1-ErbB2 heterodimers in a nontumorigenic breast epithelial cell line, MCF-10A, without interference from endogenous ErbB receptors. Using such a method, we show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers were equally potent in activating the Ras/mitogen-activated protein kinase pathway, the heterodimers were more potent in activating the phosphoinositide 3′-kinase (PI3K) and phospholipase Cγ1 pathways than ErbB2 homodimers. We combined the dimerization system with a three-dimensional cell culture approach to show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers induced disruption of three-dimensional acini-like structures, only heterodimers promoted invasion of cells through extracellular matrix. The ability of heterodimers to induce invasion required the ErbB1 kinase activity and required activation of PI3K, Ras/mitogen-activated protein kinase, and phospholipase Cγ1 signaling pathways. Thus, we have identified cell invasion as a heterodimer-specific biological outcome and suggest that coexpression of ErbB1 may critically regulate invasive progression of ErbB2-positive breast cancers. (Cancer Res 2006; 66(10): 5201-8)