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

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.