The relationship between oestrogen and epidermal growth factor receptors in human breast cancer

A consistent observation in human breast cancer is the finding of an inverse relationship between ER and EGFR. The mechanisms responsible for this are not fully understood. To investigate this further the techniques of immunocytochemistry and molecular biology have been employed to study human breast cancer. Immunocytochemical assays confirmed the inverse relationship between ER and EGFR. ER was associated with favourable and EGFR with adverse prognostic features. Further analysis suggested that loss of ER is more important than gaining EGFR in determining these associations. The development of a dual immunocytochemical assay for ER and EGFR revealed that these receptors were mutually exclusive within individual cancer cells m vivo in tumours categorised to be positive for both. This suggests the existence of separate clonal populations in some breast cancers either derived from different cell lines or arising by epigenetic mechanisms given appropriate growth conditions. DNA investigations implicate epigenetic mechanisms as amplification or rearrangement was not observed for either receptor. Hence, genomic alterations are unlikely to contribute to the inverse relationship or to the finding of separate clonal populations. RNA investigations revealed a correlation between ER protein and transcript levels suggesting that ER expression is determined either by transcriptional modulation or by increased transcript stability. EGFR protein and transcript levels were also correlated. However, EGFR protein was not detected in 44.4% of the cases containing EGFR transcripts. This was more marked in ER positive cases suggesting that EGFR expression is modulated at various molecular biological sites with the ER system possibly negatively influencing this at the translational or posttranslational level. In conclusion, the inverse relationship is likely to result from ER either negatively modulating EGFR at translation or by decreasing EGFR protein stability. Autocrine or paracrine mechanisms are implicated as separate groups of ER positive and EGFR positive cells can co-exist