Crosstalk between estrogen receptor and mitogen-activated protein kinase signaling in the development and progression of endometrial cancer

Abstract

Objective: The objectives of the study were to evaluate the role of mitogen-activated protein kinase (MAPK) signaling in normal, hyperplastic, and neoplastic endometrium in relation to estrogen receptor (ER) status and to investigate whether 17β-estradiol (E 2) and tamoxifen (TAM) mediate the proliferation and apoptosis of endometrial cancer cells through the MAPK pathway. Methods: The expressions of phosphorylated and total extracellular signalYregulated kinases 1/2 (phosphorylated extracellular signal - regulated kinase 1/2 [p-ERK1/2] and total ERK1/2 [t-ERK1/2]) were analyzed with immunohistochemistry in normal, hyperplastic, and neoplastic endometrium. The expression levels of p-ERK1/2 and t-ERK1/2 in RL95-2 and KLE after stimulation by E 2, progesterone (P), and TAM were detected by Western blotting. The effects of E 2 and TAM in combination with MAPK pathway inhibitors on the growth and apoptosis of endometrial cancer cells were examined by the MTS assay and flow cytometry analysis. Results: The expression level of p-ERK1/2 was significantly associated with the International Federation of Gynecology and Obstetrics stage (P = 0.0072). The ratio of phosphorylated/total ERK1/2 was higher in ER-positive endometrial cancer tissues and cells (P <0.05). 17β-Estradiol increased ERK1/2 phosphorylation, and TAM decreased ERK1/2 phosphorylation in endometrial cancer cell lines within 30 minutes (P < 0.05). The MEK1/2 inhibitor, U0126, and the stress-activated protein kinase/c-Jun NH 2-terminal kinase inhibitor, SP600125, significantly suppressed the proliferation of human endometrial cancer cell lines RL95-2 and KLE induced by E 2 (P < 0.05). The level of TAM-induced apoptosis was greater in KLE than in RL95-2 cells, and the p38 cascade was involved in the TAM-induced apoptosis of both cell lines (P < 0.05). Conclusions: The cross-talk between MAPK signaling and ER status might exert a key role in progression of endometrial cancer. Furthermore, the effects of E 2 or TAM on the proliferation or apoptosis of ER-positive and ER-negative endometrial cancer cells were mediated through distinct MAPK pathways. These mechanisms might contribute to ERspecific differences in MAPK activation for molecular-target therapies in endometrial carcinoma. Copyright © 2011 by IGCS and ESGO.