N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.
N-cadherin/FGFR promotes metastasis through epithelial-to-mesenchymal transition and stem/progenitor cell-like properties.
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作者：
发现N-cadherin和HER 2/neu在浸润性乳腺癌中共表达。为了测试N-钙粘蛋白和HER 2在乳腺肿瘤转移中的作用，我们靶向MMTV-Neu小鼠乳腺上皮中的N-钙粘蛋白表达。在ErbB 2/Neu的背景下，N-cadherin促进癌细胞的侵袭、增殖和转移。N-钙粘蛋白引起成纤维细胞生长因子受体（FGFR）上调，导致上皮-间充质转化（EMT）和干细胞/祖细胞样特性，涉及Snail和Slug上调、乳腺球形成和醛脱氢酶活性。FGFR的N-钙粘蛋白增强刺激细胞外信号调节激酶（ERK）和蛋白激酶B（AKT）磷酸化，导致对转移的不同作用。虽然ERK抑制抑制细胞周期蛋白D1的表达，细胞增殖和干/祖细胞的特性，它不影响入侵或EMT。相反，AKT抑制通过Akt 2衰减抑制侵袭，EMT通过Snail抑制，但对细胞周期蛋白D1表达、细胞增殖或乳腺球形成没有影响。这些发现表明，N-cadherin/FGFR通过ERK和AKT的差异调节在促进转移中具有关键作用，并强调了在晚期ErbB 2扩增的乳腺肿瘤中靶向FGFR的潜力。
N-cadherin and HER2/neu were found to be co-expressed in invasive breast carcinomas. To test the contribution of N-cadherin and HER2 in mammary tumor metastasis, we targeted N-cadherin expression in the mammary epithelium of the MMTV-Neu mouse. In the context of ErbB2/Neu, N-cadherin stimulated carcinoma cell invasion, proliferation and metastasis. N-cadherin caused fibroblast growth factor receptor (FGFR) upmodulation, resulting in epithelial-to-mesenchymal transition (EMT) and stem/progenitor like properties, involving Snail and Slug upregulation, mammosphere formation and aldehyde dehydrogenase activity. N-cadherin potentiation of the FGFR stimulated extracellular signal regulated kinase (ERK) and protein kinase B (AKT) phosphorylation resulting in differential effects on metastasis. Although ERK inhibition suppressed cyclin D1 expression, cell proliferation and stem/progenitor cell properties, it did not affect invasion or EMT. Conversely, AKT inhibition suppressed invasion through Akt 2 attenuation, and EMT through Snail inhibition, but had no effect on cyclin D1 expression, cell proliferation or mammosphere formation. These findings suggest N-cadherin/FGFR has a pivotal role in promoting metastasis through differential regulation of ERK and AKT, and underscore the potential for targeting the FGFR in advanced ErbB2-amplified breast tumors.
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