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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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Author

Summary, in English

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 Ca(2+)-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.

Department/s

Publishing year

2013-10

Language

English

Pages

83-870

Publication/Series

Molecular Oncology

Volume

7

Issue

5

Document type

Journal article

Publisher

Elsevier

Topic

  • Cancer and Oncology

Keywords

  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • MAP Kinase Signaling System
  • Matrix Metalloproteinase 9
  • Proto-Oncogene Proteins
  • Wnt Proteins
  • cdc42 GTP-Binding Protein

Status

Published

Research group

  • Experimental Pathology, Malmö

ISBN/ISSN/Other

  • ISSN: 1574-7891