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Hum. Reprod. Advance Access published online on May 20, 2008
Human Reproduction, doi:10.1093/humrep/den087
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A low concentration of genistein induces estrogen receptor-alpha and insulin-like growth factor-I receptor interactions and proliferation in uterine leiomyoma cells

X. Di, L. Yu, A.B. Moore, L. Castro, X. Zheng, T. Hermon and D. Dixon*

Comparative Pathobiology Group, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, PO Box 12233, MDC2-09, Research Triangle Park, NC 27709, USA

* Correspondence address. Tel: +1-919-541-3814; Fax: +1-919-541-0637; E-mail: dixon{at}niehs.nih.gov

BACKGROUND: Previously, we found that genistein at low concentrations stimulates the growth of human uterine leiomyoma (LM) cells, but not uterine smooth muscle (myometrial) cells (SMC). The aim of this study was to understand the molecular mechanism whereby genistein causes hyperproliferation of LM cells.

METHODS: The effects of genistein at 1 µg/ml on LM cells and SMC were evaluated using estrogen response element gene reporter, real-time RT–PCR, western blot, immunoprecipitation and cell proliferation assays.

RESULTS: Elevated estrogen receptor (ER) transactivation, increased mRNA expression of early estrogen-responsive genes, progesterone receptor and insulin-like growth factor-I (IGF-I), and decreased protein levels of ER-alpha (ER{alpha}) were found in genistein-treated LM cells, but not SMC. Additionally, extracellular regulated kinase (ERK), Src homology/collagen (Shc) and ER{alpha} were transiently activated, and interactions between ER{alpha} and IGF-I receptor (IGF-IR) were rapidly induced by genistein in LM cells. Using ER antagonist ICI 182,780 and MAPK/ERK kinase (MEK) inhibitor PD98059, we found that these early events were inhibited and the proliferative effect of genistein on LM cells was abrogated.

CONCLUSIONS: ER{alpha} is involved in the transient activation of ERK/mitogen activated protein kinase (MAPK) by genistein via its early association with IGF-IR, leading to hyper-responsiveness of LM cells and confirming that ER signaling is enhanced by activation of ERK/MAPK in LM cells.

Key words: Genistein/LM cells/SMC/ER{alpha}/IGF-IR

Submitted on June 6, 2007; resubmitted on February 12, 2008; accepted on February 27, 2008.


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