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Attenuation of Mitogen- and Stress-Activated Protein Kinase-1–Driven Nuclear Factor-B Gene Expression by Soy Isoflavones Does Not Require Estrogenic Activity

¹ Laboratory for Eukaryotic Gene Expression and Signal Transduction, Department of Molecular Biology, Ghent University, Gent, Belgium and ² Laboratorium voor Moleculaire Diagnostiek, H.-Hartziekenhuis, Roeselare, Belgium

Requests for reprints: Wim Vanden Berghe, Laboratory for Eukaryotic Gene Expression and Signal Transduction 11HB, Department of Molecular Biology, Universiteit Gent, K.L. Ledeganckstraat 35, B-9000 Gent, Belgium. Phone: 32-9-264-51-47; Fax: 32-9-264-53-04; E-mail: w.vandenberghe{at}ugent.be.

We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-B (NF-B)–driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)–deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-B transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-B p65 and histone H3 phosphorylation. As constitutive NF-B and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy. (Cancer Res 2006; 66(9): 4852-62)

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