Journal Article

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

Prasad, Chandra Prakash, Axelsson, Lena, Chaurasiya, Shivendra Kumar, Andersson, Tommy

2013

Overview

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. •A controversy exists regarding the role of WNT-5A in breast cancer cell migration.•Surprisingly, WNT-5A-induced Cdc42 activation leads to decreased breast cancer cell migration and invasion.•WNT-5A triggers cross-talk between Cdc42 and ERK1/2 thereby regulating MMP9 activity.•WNT-5A mediates a tumor suppressor effect on breast cancer cells.

• Publisher: Elsevier B.V,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Apoptosis / Breast cancer / Breast carcinoma / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Calcium / Cancer and Oncology / Cancer och onkologi / Cdc42 / cdc42 GTP-Binding Protein - genetics / cdc42 GTP-Binding Protein - metabolism / Cdc42 protein / Cell adhesion & migration / Cell division / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cell Movement - physiology / Clinical Medicine / ERK1/2 / Extracellular signal-regulated kinase / Female / Fluorescent Antibody Technique / Gelatinase B / Humans / Immunoblotting / Invasiveness / Klinisk medicin / Ligands / MAP Kinase Signaling System - genetics / MAP Kinase Signaling System - physiology / Matrix metalloproteinase / Matrix Metalloproteinase 9 - genetics / Matrix Metalloproteinase 9 - metabolism / Medical and Health Sciences / Medicin och hälsovetenskap / Melanoma / Metalloproteinase / Metastases / MMP9 / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / siRNA / Skin cancer / Studies / Tumors / Wnt protein / Wnt Proteins - genetics / Wnt Proteins - metabolism / WNT-5A / Wnt-5a Protein