ERK signalling in metastatic human MDA-MB-231 breast carcinoma cells is adapted to obtain high urokinase expression and rapid cell proliferation

Increased urokinase plasminogen activator (u-PA) production is associated w ith tumor invasion and metastasis in several malignancies, including breast cancer. The mechanisms underlying constitutive u-PA expression are not wel l understood. We examined the relationship between the signal strength of t he ERK pathway and the level of u-PA expression in the metastatic human bre ast cancer cell line MDA-MB-231. Treatment with the MEK1 inhibitor PD98059 resulted in decreased ERK1/2 phosphorylation and decreased u-PA mRNA and pr otein expression. Inhibition of ERK1/2 activity also led to decreased cell proliferation and to decreased cyclin D1 expression. Less than 5% of total ERK1/2 was phosphorylated in exponentially growing MDA-MB-231 cells, and ER K1/2 activity could be stimulated by okadaic acid. Okadaic acid did not sti mulate u-PA expression, but induced strong expression of the cdk-inhibitor p21Cip1. These findings suggest that ERK1/2 signaling is tuned to a level w hich results in high u-PA expression and rapid cell proliferation.