Fujimoto J

Tissue Differences in the Expression of mRNAs of Ha-ras, c-myc, fos and jun in Human Uterine Endometrium, Myometrium and Leiomyoma under the Influence of Estrogen/Progesterone

Ha-ras expression level in uterine endometrium (EM) in the proliferative phase (PP) was significantly higher than that in the secretory phase (SP). c-myc expressions were detected in EM, uterine myometrium (MM) and uterine leiomyoma (LM) without any cyclic change; fos expressions in LM, MM, and EM were detectable in PP, but not in SP. jun expression level in LM was significantly higher than that in MM and EM in PP, but did not alter during the menstrual cycle. Estrogen elevated the levels of Ha-ras and fos mRNAs in the three tissues, jun mRNA in MM and EM, and c-myc mRNA in LM and MM. These results suggest that there is a tissue difference in the expression of Ha-ras, c-myc, fos and jun among EM, MM and LM, under the influence of estrogen/progesterone.

Biological implications of estrogen and androgen effects on androgen receptor and its mRNA levels in human uterine endometrium

It has been shown that some effects of testosterone are different from those of its 5 alpha-reduced metabolite, dihydrotestosterone. Briefly, activities of testosterone might be related to cellular differentiation, whereas dihydrotestosterone acts on cellular proliferation. The number of testosterone binding sites in the uterine endometrium was increased by estradiol dipropionate, and this increase was down-regulated by testosterone cypionate. Dihydrotestosterone-specific binding sites in the endometrium were not modulated by estradiol dipropionate and testosterone cypionate. The dissociation constants of the binding sites for testosterone and dihydrotestosterone were not altered by these steroids. Estradiol dipropionate with or without testosterone cypionate induced androgen receptor mRNA expression in the endometrium. In conclusion, testosterone might predominantly affect cellular differentiation in the endometrium.

Expression of Aberrant Estrogen Receptor mRNA in Endometrial Cancers in Comparison with Normal Endometria

In endometrial cancers, some overexpression of estrogen receptor (ER) mRNA occurred in comparison with the ER mRNA level in normal endometria. DNA binding domains (DBDs) of ER mRNA were detected in 100% (13/13) of the endometrial cancers, and a mutated ER-DBD mRNA was found in 3 of the 13 by S1 nuclease protection analysis. It is suggested that estrogen might lead to disorder in the promotion of estrogen-inducible proteins in these 3 endometrial cancers, which seem to have a point-mutated DBD of the ER and a functional steroid-binding domain, resulting in the dedifferentiation of the original cells, and that the development and growth of cancer cells might, in part, be driven by estrogen.

Danazol decreases transcription of estrogen receptor gene in human monocytes

1. Administration of danazol for over one month reduced the levels of estrogen receptor (ER) and its mRNA to approximately 50 and 20%, respectively in monocytes. 2. Danazol did not alter the degradation rate of ER mRNA in monocytes. 3. Danazol decreased the transcription rate of ER gene to approximately 50% in monocytes in a run-on assay. 4. Danazol may release estrogen predominance via the reduction of transcription for ER gene, which leads to the reduction of ER mRNA and ER expressions in monocytes.

Estrogen induces c-Ha-ras expression via activation of tyrosine kinase in uterine endometrial fibroblasts and cancer cells.

Endometrial fibroblasts derived from uterine endometrium as controls and endometrial cancer cells (Ishikawa and HHUA cells) were used to analyze the manner of induction of c-Ha-ras transcripts in endometrial cancers, some of which are estrogen-dependent in growth. Estrogen increased c-Ha-ras expression and tyrosine kinase (TK) activity in fibroblast and Ishikawa cells, but not in HHUA cells. Progesterone diminished c-Ha-ras expression and tyrosine kinase (TK) activity induced by estradiol in the fibroblasts, but not in Ishikawa cells, which persistently overexpressed c-Ha-ras. In these cells, epidermal growth factor (EGF) increased c-Ha-ras expression as did estradiol. Pretreatment with tyrphostin, an inhibitor of TK, abolished estrogen-inducible overexpression of c-Ha-ras. The combination of both estradiol and EGF at maximum effective concentration exerted no additive or synergistic effect on induction of c-Ha-ras expression. In conclusion, persistent activation of TK might lead to overexpression of c-Ha-ras in some endometrial cancer cells under estrogen predominant milieu, which might be associated with the transformation or growth potential.

Oestrogen Induces C-Ha-Ras Expression in the Fibroblasts Derived from Human Uterine Endometrium

In this preliminary study, fibroblasts derived from uterine endometrium as a substitute for normal endometrial stroma were used to analyse the stromal role in uterine endometrium, which depends on oestrogen for growth. C-Ha-ras expression and tyrosine kinase (TK) activity in the fibroblasts were increased by oestradiol, and the increase was diminished by progesterone. Epidermal growth factor (EGF), an activator of TK, also increased c-Ha-ras expression. The combination of both oestradiol and EGF at maximum effective concentration exerted no additive and synergistic effect on induction of c-Ha-ras expression. Pretreatment with tyrphostin, an inhibitor of TK, abolished the oestrogen-inducible expression of c-Ha-ras. Oestrogen might lead to rapid induction of c-Ha-ras expression in endometrial stroma, at least in part, via the activation of TK for the early stages of oestrogen dependent growth in endometrium.