WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of breast cancer cells

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• 作者：Ch ; ra Prakash Prasad ; Shivendra Kumar Chaurasiya ; Lena Axelsson ; Tommy Andersson
• 关键词：WNT-5A ; Breast cancer ; Cdc42 ; ERK1/2 ; MMP9
• 刊名：Molecular Oncology
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：7
• 期：5
• 页码：870-883
• 全文大小：1702 K

文摘

An important role for WNT-5A is implicated in a variety of tumors, including breast carcinoma. We previously showed that WNT-5A signaling inhibits migration and metastasis of breast cancer cells, and that patients with primary breast cancer in which WNT-5A was expressed have a better prognosis. Despite the fact that RhoGTPase Cdc42 is commonly associated with increased cell migration, we here show that recombinant WNT-5A activates the Cdc42 in breast cancer cells (lines MDA-MB468 and MDA-MB231) in a time-dependent manner. Activation of Cdc42 was also observed in MDA-MB468 cells that were stably transfected with a WNT-5A plasmid (MDA-MB468-5A). In all situations, increased Cdc42 activity was accompanied by decreased migration and invasion of the breast cancer cells. To explore these findings further we also investigated the effect of WNT-5A signaling on ERK1/2 activity. Apart from an initial Ca²⁺-dependent rWNT-5A-induced activation of ERK1/2, Cdc42 activity was inversely correlated with ERK1/2 activity in both rWNT-5A-stimulated parental MDA-MB468 and MDA-MB468-5A cells. We also demonstrated increased ERK1/2 activity in MDA-MB468-5A cells following siRNA knockdown of Cdc42. Consistent with these results, breast cancer cells transfected with constitutively active Cdc42 exhibited reduced ERK1/2 activity, migration and invasion, whereas cells transfected with dominant negative Cdc42 had increased ERK1/2 activity in response to rWNT-5A. To gain information on how ERK1/2 can mediate its effect on breast cancer cell migration and invasion, we next investigated and demonstrated that WNT-5A signaling and constitutively active Cdc42 both decreased matrix metalloproteinase 9 (MMP9) activity. These data indicate an essential role of Cdc42 and ERK1/2 signaling and MMP9 activity in WNT-5A-impaired breast cancer cells.