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.
Fujimoto
J
J
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan.
Ichigo
S
S
Hori
M
M
Morishita
S
S
Tamaya
T
T
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics; D000328:Adult; D001483:Base Sequence; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D011374:Progesterone / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)