PEPTIDE GROWTH-FACTORS ELICIT ESTROGEN RECEPTOR-DEPENDENT TRANSCRIPTIONAL ACTIVATION OF AN ESTROGEN-RESPONSIVE ELEMENT

Epidermal growth factor (EGF) elicits estrogen receptor (ER)-dependent physiological sequelae and estrogen-like biochemical effects on the E R in the mouse uterus. These in vivo observations indicate that EGF ma y elicit some of its actions by activation of the ER. The effect of pe ptide growth factors on activation of a consensus estrogen-responsive element was assessed in a strain of Ishikawa human endometrial adenoca rcinoma cells with negligible levels of ERs, as determined by Western blot and [H-3]estradiol binding, and in BG-1 human ovarian adenocarcin oma cells, which contain abundant ERs. EGF and transforming growth fac tor-alpha induced transcriptional activation of a consensus ERE in an ER-dependent manner in both cell types. Transcriptional activation by the growth factors was inhibited by ICI 164,384, an ER receptor antago nist, and neutralizing antibodies to the EGF receptor. Immunodetection of the ER in BG-1 cells demonstrated that receptor levels were not in duced by transforming growth factor-alpha vs. untreated cells. ER dele tion mutants containing amino acids 1-339 and 121-599 were transfected into Ishikawa cells. The 1-339 mutant was more active in inducing tra nscription after EGF treatment than the 121-599 mutant. Estrogen only stimulated transcription in the presence of the 121-599 mutant, while 1-339 was inactive. Interestingly, synergism between a physiological d ose of estrogen and peptide growth factors was observed. The presence of cross-talk between EGF receptor and ER signaling pathways suggests that interactions between growth factors and steroid receptors may mod ulate hormonal activity influencing normal and aberrant function in ma mmalian cells.