CROSS-TALK BETWEEN PEPTIDE GROWTH-FACTOR AND ESTROGEN-RECEPTOR SIGNALING SYSTEMS

Epidermal growth factor reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estroge n-induced growth and differentiation. The mechanism by which the actio ns of estrogens and epidermal growth factor (EGF) converge is unknown. The studies described herein were performed to investigate the possib ility that some of the actions of EGF may be mediated through the estr ogen receptor. A specific estrogen receptor (ER) antagonist inhibited estrogenlike effects of EGF in the mouse uterus, specifically inductio n of DNA synthesis and phosphatidylinositol turnover. in addition, EGF elicited enhanced nuclear localization of uterine ER and formation of a unique nuclear form of ER that is present after estrogen treatment. These in vivo observations indicated that EGF may elicit some of its actions by activation of nuclear ER. Thus, the effect of peptide growt h factors on activation of a consensus estrogen response element was a ssessed in Ishikawa human endometrial adenocarcinoma cells, which cont ain negligible ER levels, and in BG-1 human ovarian adenocarcinoma cel ls, which contain abundant ER. EGF and TGF alpha induced transcription al activation of a consensus estrogen response element (ERE) in an ER- dependent manner in both cell types. In addition, insulinlike growth f actor 1 (IGF-I) was as potent as 17 beta-estradiol in BG-1 cells. Syne rgism between growth factors and estrogen was observed in both cell ty pes, although synergism was not observed between the different classes of growth factors [i.e., transforming growth factor alpha (TGF alpha) and IGF-I] in BG-1 cells. The most potent activator of ERE-dependent transcription was a protein kinase C activator (TPA), which acted syne rgisticaily with 17 beta-estradiol. A protein kinase C inhibitor aboli shed the effect of TPA but not that of 17 beta-estradiol, IGF-I, or TG F alpha. A protein kinase A activator elicited ER-dependent activation of transcription and did not synergize with estrogen or growth factor s. in conclusion, some physiologic actions of peptide growth factors a re dependent on ER. indeed, growth factors are capable of eliciting ER -dependent activation of an ERE. Both the protein kinase A and protein kinase C pathways can elicit ER-dependent transcriptional activation; however, it is unlikely that these pathways mediate the effects of pe ptide growth factors on the ER in BG-1 cells.