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Cell Growth & Differentiation Vol. 11, 99-110, February 2000
© 2000 American Association for Cancer Research


Articles

Inhibition of Mitogen-activated Protein Kinase and Phosphatidylinositol 3-Kinase Activity in MCF-7 Cells Prevents Estrogen-induced Mitogenesis1

Edward K. Lobenhofer, Gudrun Huper, J. Dirk Iglehart and Jeffrey R. Marks2

Department of Pathology [E. K. L., J. R. M.], Program in Cell and Molecular Biology [E. K. L., J. R. M.], and the Department of Surgery [G. H., J. D. I., J. R. M.], Duke University Medical Center, Durham, North Carolina 27710

Abstract

Estrogen acts to promote DNA synthesis in the MCF-7 human breast cancer cell line via its interaction with high levels of estrogen receptor. The primary mode of estrogen action has been considered to be through transcriptional activation of genes containing estrogen response elements, including the immediate early genes c-myc and fos. Recent reports have indicated that estrogen, acting through the estrogen receptor, is capable of inducing the mitogen-activated protein kinase (MAPK) cytoplasmic signaling cascade. In this study, specific small molecule inhibitors of MAPK and phosphatidylinositol 3-kinase activity were used to determine the influence of these cascades on estrogen-mediated mitogenesis. Phosphatidylinositol 3-kinase inhibitors, LY294002 and wortmannin, as well as inhibitors of MAPK kinase-1, PD098059 and U0126, decreased the fraction of cells entering DNA synthesis after treatment with 17ß-estradiol. These compounds did not inhibit expression of myc or fos. However, the drugs did prevent the accumulation of cyclin D1 and hyperphosphorylated retinoblastoma protein, indicating that the block occurred at, or prior to, this point in the cell cycle. Although these compounds were effective in preventing estrogen-mediated mitogenesis, the downstream kinases extracellular signal-regulated kinase 1, extracellular signal-regulated kinase 2, and protein kinase B were not activated over basal levels by estrogen treatment. These studies suggest that estrogen initiates mitogenesis by inducing the transcription of immediate early genes, but cytoplasmic signaling pathways play an important role in the control of subsequent events in the cell cycle.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2000 by the American Association of Cancer Research.