Attenuation Of Mitogen- And Stress-Activated Protein Kinase-1-Driven Nuclear Factor-Kappa B Gene Expression By Soy Isoflavones Does Not Require Estrogenic Activity

We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappa B (NF-kappa 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-kappa 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-kappa B p65 and histone H3 phosphorylation. As constitutive NF-kappa B and MSK activity are hallmarks of aggressive meta- static ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.