BIMODAL REGULATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR BY ESTROGEN INBREAST-CANCER CELLS

In breast cancer, epidermal growth factor (EGF) receptor (EGFR) expres sion is inversely correlated with expression of estrogen receptor (ER) and predicts the prognosis and failure of endocrine therapy. We repor t here, for the first time, that in ER-positive breast cancer cell lin es, MCF-7, T47D, and BT474, 17 beta-estradiol (E(2)) transiently induc ed EGFR messenger RNA (mRNA) levels 2- to 3-fold; this induction was p revented by the presence of the antiestrogen ICI 164,384 and was also reflected in the level of EGFR protein. Up-regulation of EGFR mRNA is most likely due to a direct effect of ER on the EGFR gene, with no inv olvement of protein synthesis, as it was not inhibited in the presence of cycloheximide; however, the subsequent down-regulation of EGFR req uired de novo protein synthesis. E(2) had no effect on EGFR mRNA stabi lity, and EGFR transcript levels were found to parallel EGFR mRNA leve ls, further supporting a direct transcriptional mechanism in the regul ation of EGFR expression by estrogens. Additionally, sequencing of the EGFR promoter revealed putative imperfect estrogen-responsive element s that were capable of binding human ER. The transient nature of EGFR induction by E(2), with a rapid return to a basal level that is depend ent on protein synthesis, suggests that breast cancer cells possess ac tive mechanisms to maintain low levels of EGFR expression in the prese nce of estrogen and a functional ER.