Abstract
Increased urokinase plasminogen activator (u-PA) production is associated with tumor invasion and metastasis in several malignancies, including breast cancer. The mechanisms underlying constitutive u-PA expression are not well understood. We examined the relationship between the signal strength of the ERK pathway and the level of u-PA expression in the metastatic human breast cancer cell line MDA-MB-231. Treatment with the MEK1 inhibitor PD98059 resulted in decreased ERK1/2 phosphorylation and decreased u-PA mRNA and protein 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 ERK1/2 activity could be stimulated by okadaic acid. Okadaic acid did not stimulate u-PA expression, but induced strong expression of the cdk-inhibitor p21Cip1. These findings suggest that ERK1/2 signaling is tuned to a level which results in high u-PA expression and rapid cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast Neoplasms / enzymology*
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Breast Neoplasms / pathology*
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Breast Neoplasms / secondary
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Cell Division / physiology
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Cyclin D1 / biosynthesis
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Cyclin D1 / genetics
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic
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Humans
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 1 / physiology
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Mitogen-Activated Protein Kinases / physiology
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Neoplasm Metastasis
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Okadaic Acid / pharmacology
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-jun / biosynthesis
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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Proto-Oncogene Proteins c-raf / physiology
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Tumor Cells, Cultured
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Urokinase-Type Plasminogen Activator / biosynthesis*
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Flavonoids
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Proto-Oncogene Proteins c-jun
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Cyclin D1
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Okadaic Acid
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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Urokinase-Type Plasminogen Activator
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one