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This version published online on March 31, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0278
A more recent version of this article appeared on July 1, 2004
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Submitted on July 16, 2003
Accepted on March 23, 2004

Antiestrogens induce growth inhibition by sequential activation of p38 MAP-kinase and TGF{beta} pathways in human breast cancer cells

Miriam B. Buck, Klaus Pfizenmaier, and Cornelius Knabbe*

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Institute of Cell Biology and Immunology, University of Stuttgart, Germany; Robert Bosch Hospital, Department of Laboratory Medicine, Stuttgart, Germany

* To whom correspondence should be addressed. 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 MAP-kinase inhibitors and MCF-7 carcinoma cells as a model to demonstrate that p38 MAP-kinase 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.

TGF{beta}, a negative regulator of breast cancer cell growth, is induced by antiestrogens, therefore activation of p38 could have been mediated by TGF{beta}. We used a TGF{beta} and antiestrogen sensitive reporter gene assay to show that p38 activation precedes TGF{beta} activation. These results were further confirmed by quantitative RT-PCR analysis of the antiestrogen induced transcription of TGF{beta}2 and TGF{beta} receptor II. Inhibition of p38 reduced the induction of both genes.

Finally, Western blot analysis shows that antiestrogens induce phosphorylation of Smad2 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 TGF{beta} pathways to mediate growth inhibition.
Key words: antiestrogen • signal transduction • breast cancer • p38 • TGF-beta

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Coregulators:   Cyclin A1  |  SMAD3
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen



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