Identification and characterization of a negative regulatory element within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer cells.
The epidermal growth factor receptor (EGFR) exhibits an inverse correlation with estrogen receptor (ER) expression in the majority of breast cancers, predicting a poor response to endocrine therapy and poor survival rate. Inappropriate overexpression of EGFR in breast cancer is associated with a more aggressive phenotype. Transcriptional regulation is the major regulatory mechanism controlling EGFR overexpression in breast cancer cells. We have identified a region within the first intron of the EGFR gene that mediates transcriptional repression of EGFR gene expression in ER +/low EGFR expressing but not in ER-/high EGFR expressing breast cancer cells. Utilizing transient transfections of homologous and heterologous promoter-reporter constructs, we localized optimal repressive activity to a 96 bp intron domain. The 96 bp fragment displayed differential DNA-protein complex formation with nuclear extracts from ER + vs. ER- breast cancer cells. Moreover, factors interacting with this intron negative regulatory element appear to be estrogen-regulated. Consequently, our results suggest that we have identified a potential mechanism by which maintenance of low levels of EGFR expression and subsequent EGFR upregulation may be attributed to the loss of transcriptional repression of EGFR gene expression in hormone-dependent breast cancer cells.
Wilson
Melissa A
MA
Department of Biochemistry and Molecular Biology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA. wilsonme@mail.nih.gov
Chrysogelos
Susan A
SA
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D020847:Estrogen Receptor Modulators; D004967:Estrogens; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D066246:ErbB Receptors