Kim In-Young, Yong Hae-Young, Kang Keon Wook, Moon Aree
College of Pharmacy, Duksung Women's University, 419 Ssangmun-dong, Tobong-gu, Seoul, Republic of Korea.
Cancer Lett. 2009 Mar 18;275(2):227-33. doi: 10.1016/j.canlet.2008.10.013. Epub 2008 Nov 20.
Metastasis is the principal cause of death from breast cancer. ErbB2 (HER-2/neu) has been identified as an important regulator of metastatic potential of breast cancer. The present study investigated the molecular mechanism underlying the role of ErbB2 in malignant phenotypic conversion of MCF10A human breast epithelial cells which originally have 'normal' cell character. Here we report that ErbB2 induces invasion and migration of MCF10A cells though up-regulation of matrix metalloproteinase (MMP)-9. We also observed a marked reduction of an epithelial cell marker, E-cadherin, and an induction of vimentin in ErbB2-MCF10A cells, suggesting that epithelial-mesenchymal transition may play a role in the ErbB2-induced invasion and migration of MCF10A cells. Overexpression of ErbB2 significantly activated p38 MAPK and Akt, while Raf-1/MEK/ERK pathway was not activated by ErbB2. Using pharmacological inhibitors, we further show that p38 MAPK and Akt signaling pathways are crucial for the ErbB2-induced MMP-9 up-regulation, invasion and migration of MCF10A cells. Given that ErbB2 is one of the most important oncogenes in human breast cancer and thus is an attractive therapeutic target, our findings may provide a molecular basis for the promoting role of ErbB2 in breast cancer progression.
转移是乳腺癌致死的主要原因。ErbB2（HER-2/neu）已被确定为乳腺癌转移潜能的重要调节因子。本研究调查了ErbB2在原本具有“正常”细胞特征的MCF10A人乳腺上皮细胞恶性表型转化中作用的分子机制。在此我们报告，ErbB2通过上调基质金属蛋白酶（MMP）-9诱导MCF10A细胞的侵袭和迁移。我们还观察到在ErbB2-MCF10A细胞中上皮细胞标志物E-钙黏蛋白显著减少，波形蛋白诱导表达，这表明上皮-间质转化可能在ErbB2诱导的MCF10A细胞侵袭和迁移中发挥作用。ErbB2的过表达显著激活p38丝裂原活化蛋白激酶（MAPK）和Akt，而Raf-1/MEK/ERK途径未被ErbB2激活。使用药理学抑制剂，我们进一步表明p38 MAPK和Akt信号通路对于ErbB2诱导的MCF10A细胞MMP-9上调、侵袭和迁移至关重要。鉴于ErbB2是人类乳腺癌中最重要的癌基因之一，因此是一个有吸引力的治疗靶点，我们的发现可能为ErbB2在乳腺癌进展中的促进作用提供分子基础。
