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Antiestrogens Induce Growth Inhibition by Sequential Activation of p38 Mitogen-Activated Protein Kinase and Transforming Growth Factor-ß Pathways in Human Breast Cancer Cells

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology (M.B.B.), and Robert Bosch Hospital (M.B.B., C.K.), Department of Laboratory Medicine, 70376 Stuttgart, Germany; and Institute of Cell Biology and Immunology (K.P.), University of Stuttgart, 70569 Stuttgart, Germany

Address all correspondence and requests for reprints to: Cornelius Knabbe, MD, Department of Laboratory Medicine, Robert Bosch Hospital, Auerbachstrasse 110, 70376 Stuttgart, Germany. E-mail: cornelius.knabbe{at}rbk.de.

Antiestrogens are successfully used in the treatment of breast cancer. The purpose of this study was to investigate the role of different signal transduction pathways in antiestrogen-induced growth inhibition to gain insights into mechanisms of antiestrogen resistance.

We used specific MAPK inhibitors and MCF-7 carcinoma cells as a model to demonstrate that p38 MAPK is an important mediator of antiestrogen growth inhibition in breast cancer. A kinase assay showed that antiestrogens (4-hydroxytamoxifen and ICI 182.780) rapidly induce p38 activity. Overexpression of kinase-deficient mutants of p38 reduced the antiestrogen suppression of Cyclin A transcription.

TGFß, a negative regulator of breast cancer cell growth, is induced by antiestrogens; therefore, activation of p38 could have been mediated by TGFß. We used a TGFß and antiestrogen-sensitive reporter gene assay to show that p38 activation precedes TGFß activation. These results were further confirmed by quantitative RT-PCR analysis of the antiestrogen-induced transcription of TGFß2 and TGFß receptor II. Inhibition of p38 reduced the induction of both genes.

Finally, Western blot analysis shows that antiestrogens induce phosphorylation of Smad (mothers against decapentaplegic homolog) 2 via p38. Promoter assays with the Smad-dependent reporter p6SBE confirm participation of Smad3 and Smad4 in antiestrogen action.

Taken together, our data delineate an antiestrogen signal transduction pathway involving sequential activation of p38 and TGFß pathways to mediate growth inhibition.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   Cyclin A1  |  SMAD3

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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