title: 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 (E2) and tamoxifen (TAM) mediate the proliferation and apoptosis of endometrial cancer cells through the MAPK pathway.
  
  
  METHODS
  The expressions of phosphorylated and total extracellular signal-regulated 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 E2, progesterone (P), and TAM were detected by Western blotting. The effects of E2 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 NH2-terminal kinase inhibitor, SP600125, significantly suppressed the proliferation of human endometrial cancer cell lines RL95-2 and KLE induced by E2 (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 E2 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 ER-specific differences in MAPK activation for molecular-target therapies in endometrial carcinoma.
authors: Shanghai Jiao Tong University Affiliated International Peace Maternal and Child Health Hospital, Shanghai, People's Republic of China.
authors: Long
authors: L
authors: Zhou
authors: Bin
authors: B
authors: Cai
authors: Wei
authors: W
authors: Bao
authors: Yin-Yan
authors: YY
authors: He
authors: Xiao-Yue
authors: XY
authors: Chen
authors: Yi-Xia
authors: YX
authors: Yang
authors: Xue-Lian
authors: XL
authors: Liu
authors: Xiao-Ping
authors: XP
authors: Wan
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000209:etiology* / Q000378:metabolism; D004958:Estradiol; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D008875:Middle Aged; D010766:Phosphorylation; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen
chemical_list: D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol