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

• Published in: Clinical & experimental metastasis 1999-01, Vol.17 (8), p.649
• Main Authors: Seddighzadeh, M, Zhou, J N, Kronenwett, U, Shoshan, M C, Auer, G, Sten-Linder, M, Wiman, B, Linder, S
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Breast Neoplasms - secondary; Cell Division - physiology; Cyclin D1 - biosynthesis; Cyclin D1 - genetics; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Cyclins - genetics; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System - physiology; Medicin och hälsovetenskap; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Mitogen-Activated Protein Kinases - physiology; Neoplasm Metastasis; Okadaic Acid - pharmacology; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-jun - biosynthesis; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-raf - metabolism; Proto-Oncogene Proteins c-raf - physiology; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator - biosynthesis
• ISSN: 0262-0898; 1573-7276
• DOI: 10.1023/A:1006741228402

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.