Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis.
Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis.
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DOI：
10.1038/onc.2011.275
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发表时间：
2012-02-09
期刊：
影响因子：
8
通讯作者：
Segall, J. E.
中科院分区：
文献类型：
--
作者：
Smirnova, T.;Zhou, Z. N.;Flinn, R. J.;Wyckoff, J.;Boimel, P. J.;Pozzuto, M.;Coniglio, S. J.;Backer, J. M.;Bresnick, A. R.;Condeelis, J. S.;Hynes, N. E.;Segall, J. E.
许多恶性肿瘤表现为EGF受体家族成员ErbB3(HER3)表达增加。ErbB3与β-1(hrg-β1)结合，与erbB2(HER2)或eGFR(HER1)等家族成员形成异源二聚体，促进特定C末端酪氨酸残基的磷酸化，激活下游信号通路。ErbB3含有6个YXXM基序，与PI3-激酶的P85亚基结合。以往的研究表明，在乳腺肿瘤细胞中过表达ErbB3可以显著增强对hRG-β-1的趋化能力和整体转移潜能。我们验证了一种假设，即ErbB3介导的PI3-激酶信号对Hereglin诱导的运动至关重要，因此对ErbB3介导的侵袭、血管内和转移至关重要。ErbB3 C末端的6个YXXM基序中的酪氨酸被苯丙氨酸取代。与野生型ErbB3的过表达相比，突变型ErbB3的过表达在体外和体内均不能增强对HRGβ1的趋化作用。我们还通过多光子显微镜观察到原发肿瘤中肿瘤细胞活力降低，以及这些细胞穿过内皮并进入循环的能力显著降低。此外，虽然ErbB3 C末端突变对肿瘤生长没有影响，但它对自发转移潜能有显著影响。PI3-激酶抑制剂PIK-75在体外和体内的治疗类似地抑制了运动性和侵袭性。我们的结果表明，ErbB3对运动和侵袭的早期转移步骤的刺激需要ErbB3受体激活PI3-激酶途径。
Many malignancies show increased expression of the EGF receptor family member ErbB3 (HER3). ErbB3 binds beta-1 (HRGβ1), and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGFR (HER1), enhancing phosphorylation of specific C terminal tyrosine residues and activation of downstream signaling pathways. ErbB3 contains six YXXM motifs that bind the p85 subunit of PI3-kinase. Previous studies demonstrated that overexpression of ErbB3 in mammary tumor cells can significantly enhance chemotaxis to HRGβ1 and overall metastatic potential. We tested the hypothesis that ErbB3-mediated PI3-kinase signaling is critical for heregulin-induced motility, and therefore crucial for ErbB3-mediated invasion, intravasation and metastasis. The tyrosines in the six YXXM motifs on the ErbB3 C-terminus were replaced with phenylalanine. In contrast to overexpression of the wild-type ErbB3, overexpression of the mutant ErbB3 did not enhance chemotaxis towards HRGβ1 in vitro or in vivo. We also observed reduced tumor cell motility in the primary tumor by multiphoton microscopy, as well as a dramatically reduced ability of these cells to cross the endothelium and intravasate into the circulation. Moreover, while mutation of the ErbB3 C-terminus had no effect on tumor growth, it had a dramatic effect on spontaneous metastatic potential. Treatment with the PI3-kinase inhibitor PIK-75 similarly inhibited motility and invasion in vitro and in vivo. Our results indicate that stimulation of the early metastatic steps of motility and invasion by ErbB3 requires activation of the PI3-kinase pathway by the ErbB3 receptor.
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