Estrogen suppression of EGFR expression in breast cancer cells: A possiblemechanism to modulate growth

Epidermal growth factor receptor (EGFR) is a transmembrane receptor whose o verexpression in breast cancer predicts for poor prognosis and is inversely correlated with expression of estrogen receptor (ER). This study was desig ned to investigate whether estrogen plays an active role in suppression of EGFR expression in estrogen-responsive breast cancer cell lines expressing low levels of EGFR. Upon withdrawal of estrogen, EGFR mRNA and protein incr eased 3-6 fold in MCF-7, T47D, and BT474 ER+ breast cancer cells. This was reversible upon addition of estradiol back to the culture media, but only a fter prolonged treatment. Nuclear run-on assays and studies with the transc ription inhibitor actinomycin B demonstrated that regulation is at the tran scriptional level. These results indicate that in the presence oi estrogen, ER+ breast cancer cells possess active mechanisms to suppress EGFR express ion. Up-regulation of EGFR in response to estrogen depletion and growth inh ibition could represent an attempt to rescue cell growth by utilizing an al ternative pathway. Indeed, we found that estrogen-depleted breast cancer ce lls are more sensitive to the mitogenic effects of EGF and TGF-alpha, and s imultaneous blockade of both estrogen and EG FR signaling pathways induced cell death. (C) 2001 Wiley-Liss, Inc.