A number of studies suggest that an inverse correlation exists between the epidermal growth factor-receptor and the estrogen receptor expression in primary human breast carcinoma as well as in established human breast carcinoma cell lines. Recent studies suggest that the epidermal growth factor-receptor does not regulate the estrogen receptor gene expression. Whether the estrogen receptor regulates the epidermal growth factor-receptor gene expression is not known. We addressed this question by stably transfecting the estrogen receptor cDNA into the estrogen receptor-negative human breast carcinoma cell line MDA-MB-231. Constitutive expression of functional estrogen receptors in the transfectants 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 alpha mRNA levels, did not modulate epidermal growth factor-receptor mRNA levels. The estrogen receptor-transfected cells grown in estrogenic regular medium, however, exhibited lower constitutive levels of epidermal growth factor-receptor mRNA than in steroid-stripped medium, suggesting that estrogens coupled with some factors normally present in the regular medium may indeed downmodulate epidermal growth factor-receptor mRNA. Sodium butyrate treatment enhanced epidermal growth factor-receptor mRNA levels in nontransfected cells grown in regular estrogenic as well as in steroid stripped medium. Sodium butyrate enhancement of epidermal growth factor-receptor mRNA levels was completely abolished in estrogen receptor-transfected cells grown in regular estrogenic medium and blunted in steroid stripped medium. Using various epidermal growth factor-receptor gene promoter-CAT constructs in transient transfection assays, we further demonstrate that sodium butyrate enhanced transcription of the epidermal growth factor-receptor gene. The putative sodium butyrate responsive element(s) appears to localize within the proximal 384 bp of the epidermal growth factor-receptor gene promoter region. Although the interactions between estrogen receptor and epidermal growth factor-receptor are rather complex, taken together, our data suggest that estrogen receptor can indeed modulate the epidermal growth factor-receptor mRNA expression.