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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

Prasad, Chandra Prakash LU ; Chaurasiya, Shivendra Kumar LU ; Axelsson, Lena LU and Andersson, Tommy LU (2013) In Molecular Oncology 7(5). p.83-870
Abstract

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... (More)

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.

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author
organization
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type
Contribution to journal
publication status
published
subject
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
in
Molecular Oncology
volume
7
issue
5
pages
14 pages
publisher
Elsevier
external identifiers
  • Scopus:84884280193
ISSN
1574-7891
DOI
10.1016/j.molonc.2013.04.005
language
English
LU publication?
yes
id
b5408894-b5ae-4195-a9ea-688211d5809e
date added to LUP
2016-06-02 15:10:41
date last changed
2016-12-04 04:52:04
@misc{b5408894-b5ae-4195-a9ea-688211d5809e,
  abstract     = {<p>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.</p>},
  author       = {Prasad, Chandra Prakash and Chaurasiya, Shivendra Kumar and Axelsson, Lena and Andersson, Tommy},
  issn         = {1574-7891},
  keyword      = {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},
  language     = {eng},
  number       = {5},
  pages        = {83--870},
  publisher    = {ARRAY(0x9816578)},
  series       = {Molecular Oncology},
  title        = {WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of breast cancer cells},
  url          = {http://dx.doi.org/10.1016/j.molonc.2013.04.005},
  volume       = {7},
  year         = {2013},
}