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 transdu ction of extracellular signals to the cytoplasm via the receptor not only d epends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, with regard to cancer diagnosis and therapeut ic approaches targeting EGFR it is important to know how the expression lev el of EGFR is controlled. We found that transcription activity declines wit h increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the epidermal growth factor receptor gene. In vivo d ata from cultured cell lines support these findings, although other regulat ion mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence r epeat (SSR) and that there are two separate major transcription start sites . Model calculations for the helical DNA conformation revealed a high benda bility in the EGFR polymorphic region, especially if the CA stretch is exte nded. 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 ca ncel; linking genetic and epigenetic risk factors. Furthermore, in breast c ancer, heterozygous tumors with short CA-SSR showed an elevated EGFR-expres sion in contrast to tumours with longer CA-SSR. Tumours with loss of hetero zygosity in intron I of egfr revealed an increased EGFR expression if the l onger allele was lost. Moreover decreased EGFR gene levels were significant ly correlated with poor prognosis in breast cancer.