Estrogenic effect of the MEK1 inhibitor PD98059 on endogenous estrogen receptor alpha and beta

Estrogens are key regulators in mammary development and breast cancer and their effects are mediated by estrogen receptors alpha (ER alpha) and beta (ER beta). These two receptors are ligand activated transcription factors that bind to regulatory regions in the DNA known as estrogen responsive elements (EREs). ER alpha and ER beta activation is subject to modulation by phosphorylation and p42/p44 MAP kinases are the best characterized ER modifying kinases. Using a reporter gene (3X-ERE-TATA-luciferase) to measure activation of endogenous ERs, we found that MEK1 inhibitor PD98059, used in concentrations insufficient to inhibit MEK1 activation of p42/p44 MAP kinases, exerted estrogenic effects on the reporter gene and on the ERE-regulated RIP 140 protein. Such estrogenic effects were observed in mammary epithelial HC11 cells and occur on unliganded ER alpha and ligand activated ER beta. Additionally, concentrations of PD98059 able to inhibit p42/p44 phosphorylation were not estrogenic. Further, inhibition of p42 MAP kinase expression with siRNAs also resulted in loss of PD98059 estrogenic effect. In summary, PD98059 in concentrations below the inhibitory for MEK1, exerts estrogenic effects in HC11 mammary epithelial cells. (C) 2011 Elsevier Ltd. All rights reserved.