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 (ERα) and beta (ERβ). These two receptors are ligand activated transcription factors that bind to regulatory regions in the DNA known as estrogen responsive elements (EREs). ERα and ERβ 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 ERα and ligand activated ERβ. 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.

Research highlights▶ The MEK1 inhibitor PD98059 exerts estrogenic effects. ▶ PD98059 estrogenic concentrations do not inhibit MEK1. ▶ Estrogenic PD98059 activates estrogen receptor regulated promoters. ▶ These results raise awareness on the use PD98059 as specific MEK1 inhibitor. ▶ These results can be used for development of estrogen receptor selective ligands.