Modulation of EGFR gene transcription by a polymorphic repetitive sequence--a link between genetics and epigenetics.
The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation and motility of normal as well as tumor cells. The transduction of extracellular signals to the cytoplasm via the receptor not only depends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, with regard to cancer diagnosis and therapeutic approaches targeting EGFR it is important to know how the expression level of EGFR is controlled. We found that transcription activity declines with increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the epidermal growth factor receptor gene. In vivo data from cultured cell lines support these findings, although other regulation mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence repeat (SSR) and that there are two separate major transcription start sites. Model calculations for the helical DNA conformation revealed a high bendability in the EGFR polymorphic region, especially if the CA stretch is extended. These data suggest that the CA-SSR can act like a joint, bringing the promoter in proximity to a putative repressor protein bound downstream of the CA-SSR. The data indicate that this polymorphism may be a marker for cancer, linking genetic and epigenetic risk factors. Furthermore, in breast cancer, heterozygous tumors with short CA-SSR showed an elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression if the longer allele was lost. Moreover, decreased EGFR gene levels were significantly correlated with poor prognosis in breast cancer.
Gebhardt
F
F
Institute for Clinical Chemistry, University of Münster, Germany.
Bürger
H
H
Brandt
B
B
D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D066246:ErbB Receptors