EXPRESSION OF ESTROGEN-RECEPTORS IN ESTROGEN RECEPTOR-NEGATIVE HUMAN BREAST-CARCINOMA CELLS - MODULATION OF EPIDERMAL GROWTH FACTOR-RECEPTOR (EGF-R) AND TRANSFORMING GROWTH-FACTOR-ALPHA (TGF-ALPHA) GENE-EXPRESSION

A number of studies suggest that an inverse correlation exists between the epidermal growth factor-receptor and the estrogen receptor expres sion in primary human breast carcinoma as well as in established human breast carcinoma cell lines. Recent studies suggest that the epiderma l growth factor-receptor does not regulate the estrogen receptor gene expression. Whether the estrogen receptor regulates the epidermal grow th factor-receptor gene expression is not known. We addressed this que stion by stably transfecting the estrogen receptor cDNA into the estro gen receptor-negative human breast carcinoma cell line MDA-MB-231. Con stitutive expression of functional estrogen receptors in the transfact ants resulted in increased mRNA levels of both epidermal growth factor -receptor and transforming growth factor alpha. Estradiol treatment of transfected cells, although enhancing transforming growth factor alph a mRNA levels, did not modulate epidermal growth factor-receptor mRNA levels. The estrogen receptor-transfected cells grown in estrogenic re gular medium, however, exhibited lower constitutive levels of epiderma l growth factor-receptor mRNA than in steroid-stripped medium, suggest ing that estrogens coupled with some factors normally present in the r egular medium may indeed downmodulate epidermal growth factor-receptor mRNA. Sodium butyrate treatment enhanced epidermal growth factor-rece ptor mRNA levels in nontransfected cells grown in regular estrogenic a s well as in steroid stripped medium. Sodium butyrate enhancement of e pidermal growth factor-receptor mRNA levels was completely abolished i n estrogen receptor-transfected cells grown in regular estrogenic medi um and blunted in steroid stripped medium. Using various epidermal gro wth factor-receptor gene promoter-CAT constructs in transient transfec tion assays, we further demonstrate that sodium butyrate enhanced tran scription of the epidermal growth factor-receptor gene. The putative s odium butyrate responsive element(s) appears to localize within the pr oximal 384 bp of the epidermal growth factor-receptor gene promoter re gion. Although the interactions between estrogen receptor and epiderma l growth factor-receptor are rather complex, taken together, our data suggest that estrogen receptor can indeed modulate the epidermal growt h factor-receptor mRNA expression. (C) 1994 Wiley-Liss, Inc.