N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation
N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation
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DOI：
10.1158/0008-5472.can-06-3401
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Hazan, Rachel B.
中科院分区：
文献类型：
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作者：
Hulit, James;Suyama, Kimita;Hazan, Rachel B.
N-钙粘蛋白在侵袭性乳腺癌中上调，但其体内作用机制尚不清楚。在乳腺上皮共表达N-钙粘蛋白和多瘤病毒中T抗原（PyVmT）的转基因小鼠显示肺转移增加，与对照PyVmT小鼠相比，肿瘤发生或生长无差异。与PyVmT对照组相比，PyVmT-N-钙粘蛋白肿瘤中磷酸化细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（MAPK）的水平更高，并且磷酸化ERK染色在肺转移瘤中进一步增加。与PyVmT对照组相比，PyVmT-N-钙粘蛋白小鼠的肿瘤细胞分离物表现出增强的ERK激活、运动性、侵袭性和基质金属蛋白酶-9（MMP-9）表达。MAPK/ERK激酶1抑制PyVmT-N-钙粘蛋白细胞中MMP-9的产生和侵袭，但不运动。此外，PyVmT-N-钙粘蛋白细胞中成纤维细胞生长因子受体的失活降低了运动性、侵袭性和ERK激活，但对PyVmT细胞没有影响。因此，乳腺导管中N-钙粘蛋白的从头表达通过增强的ERK信号传导增强乳腺肿瘤的转移。
N-cadherin is up-regulated in aggressive breast carcinomas, but its mechanism of action in vivo remains unknown. Transgenic mice coexpressing N-cadherin and polyomavirus middle T antigen (PyVmT) in the mammary epithelium displayed increased pulmonary metastasis, with no differences in tumor onset or growth relative to control PyVmT mice. PyVmT-N-cadherin tumors contained higher levels of phosphorylated extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) than PyVmT controls, and phosphorylated ERK staining was further increased in pulmonary metastases. Tumor cell isolates from PyVmT-N-cadherin mice exhibited enhanced ERK activation, motility, invasion, and matrix metalloproteinase-9 (MMP-9) expression relative to PyVmT controls. MAPK/ERK kinase 1 inhibition in PyVmT-N-cadherin cells reduced MMP-9 production and invasion but not motility. Furthermore, inactivation of fibroblast growth factor receptor in PyVmT-N-cadherin cells reduced motility, invasion, and ERK activation but had no effect on PyVmT cells. Thus, de novo expression of N-cadherin in mammary ducts enhances metastasis of breast tumors via enhanced ERK signaling.