Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth.
Epidermal growth factor receptor (EGFR) is a transmembrane receptor whose overexpression in breast cancer predicts for poor prognosis and is inversely correlated with expression of estrogen receptor (ER). This study was designed 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 increased 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 after prolonged treatment. Nuclear run-on assays and studies with the transcription inhibitor actinomycin D demonstrated that regulation is at the transcriptional level. These results indicate that in the presence of estrogen, ER+ breast cancer cells possess active mechanisms to suppress EGFR expression. Up-regulation of EGFR in response to estrogen depletion and growth inhibition could represent an attempt to rescue cell growth by utilizing an alternative pathway. Indeed, we found that estrogen-depleted breast cancer cells are more sensitive to the mitogenic effects of EGF and TGF-alpha, and simultaneous blockade of both estrogen and EGFR signaling pathways induced cell death. J. Cell. Biochem. Suppl. 36: 232-246, 2001.
Yarden
R I
RI
Department of Oncology, Georgetown University, Washington, DC 20007, USA.
Wilson
M A
MA
Chrysogelos
S A
SA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020847:Estrogen Receptor Modulators; D004967:Estrogens; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors