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WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of
Chandra Prakash Prasad1, Shivendra Kumar Chaurasiya, Lena Axelsson
1Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
Molecular Oncology
|June 4, 2013
Summary
WNT-5A signaling activates Cdc42 (a protein linked to cell migration) in breast cancer cells, paradoxically reducing their migration and invasion. This pathway also impacts ERK1/2 activity and matrix metalloproteinase 9 (MMP9) activity.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- WNT-5A signaling is implicated in various cancers, including breast carcinoma.
- Previous studies indicated WNT-5A inhibits breast cancer cell migration and metastasis, correlating with better patient prognosis.
- Rho GTPase Cdc42 is typically associated with increased cell migration, presenting a potential paradox with WNT-5A's observed effects.
Purpose of the Study:
- To investigate the role of WNT-5A in activating Cdc42 in breast cancer cells.
- To elucidate the relationship between WNT-5A, Cdc42, ERK1/2 activity, and breast cancer cell migration/invasion.
- To determine the involvement of matrix metalloproteinase 9 (MMP9) in WNT-5A-mediated effects on breast cancer.
Main Methods:
- Recombinant WNT-5A stimulation of breast cancer cell lines (MDA-MB468, MDA-MB231).
- Stable transfection of MDA-MB468 cells with WNT-5A plasmid (MDA-MB468-5A).
- Analysis of Cdc42 and ERK1/2 activity, cell migration, invasion assays, siRNA knockdown, and MMP9 activity assessment.
Main Results:
- Recombinant WNT-5A and stable WNT-5A expression activated Cdc42 in breast cancer cells.
- Increased Cdc42 activity correlated with decreased cell migration and invasion.
- WNT-5A signaling modulated ERK1/2 activity, which was inversely correlated with Cdc42 activity, and both pathways reduced MMP9 activity.
Conclusions:
- WNT-5A signaling activates Cdc42 in breast cancer cells, leading to reduced migration and invasion.
- The interplay between Cdc42 and ERK1/2 signaling, along with MMP9 activity, is crucial for WNT-5A's tumor-suppressive effects.
- These findings highlight a novel mechanism by which WNT-5A can impair breast cancer progression.
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