Analysis of the molecular mechanisms of the estrogen-dependent growth of the endometrial carcinoma

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The growth of the normal human endometrium and estrogen receptor ( ER ) -positive endometrial carcinoma is stimulated by estrogen via ER.Recent studied have revealed that the cell cycle-related molecules, such a cyclins, cyclin dependent kinases ( cdk ), and cdk inhabitors ( cdkI ) play essential roles in cell proliferation. The present study was undertaken to incestigate the possible involvement of the cell cycle-related molecules in estogen-dependent growth of the normal and neoplastic endometrium.Immunohistochemical staining demonstrated that in the normal endometrial glands, cyclins ( D1, E, A, B1 ) and cdks ( cdk4, cdk2, cdc2 ) were sporadically expressed in the proliferative phase, and were overexpressed in 30-75 % of the endometrialcarcanoma examined. Overexpression of cylin A and cdk4 wa correlated with patients' survival.The molecular mechanisms for the estrogen-induced growth of the endometriaum was analyzed using cultured glandular cells from normal proliferative endometrium … More with or without estradiol ( E_2 ) stimulation. Expression of cyclin D1 was detected 4 hours after E_2 treatment, and followed by serial expressions of cyclin E, A, and B1. For the intracellur pathway of cyclin D1 up-regulation by estrogen, we hypothesized the involvement of transcription factor, c-Jun/c-Fos, since te cyclin D1 posess c-Jun/c-Fos binding ( AP-1 ) site but lacks the estrogen responsive element. The expression of c-Jun in cultured endometrial cell occurred 2 hours after E_2 stimulation., preceding the cyclin D1 expression. Luciferase assay using various cyclin D1 promoter constructs revealed that the elecated luciferase activity afterE, stimulation was observed exclusively in the costructs possessing AP-1 site. Gel shift mobility assay indicated the binding of AP-1 bining site to nuclear extracts from E_2 treated endometrial epithelia. Increased luciferas activity was also observed when c-Jun expression plasmid was co-transfected with containing AP-1 site. On the other hand, inER-positive endometrial carcinoma ( Ishikawa ) cells, the expression pattern cyclins after E_2 stimulation as well as promoter activity of cyclin D1 differed from those of te normal endometrial cells. These findings seggested that the estrogen-stimulated expression of cyclin D1 in the normal endometrial glands is mediated by AP-1, and that was different from ER-positive endometrial carcinoma. Less