WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of breast cancer cells
(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.
(Less)
- author
- Prasad, Chandra Prakash LU ; Chaurasiya, Shivendra Kumar LU ; Axelsson, Lena LU and Andersson, Tommy LU
- organization
- publishing date
- 2013-10
- 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
- wos:000325668200002
- pmid:23727359
- 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
- 2024-04-05 00:17:06
@article{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}}, 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}}, language = {{eng}}, number = {{5}}, pages = {{83--870}}, publisher = {{Elsevier}}, 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}}, doi = {{10.1016/j.molonc.2013.04.005}}, volume = {{7}}, year = {{2013}}, }