Investigation of the mechanisms determining the inverse relationship between oestrogen and epidermal growth factor receptors in primary human breast cancer

Abstract

One of the most consistent observations in the investigation of human breast cancer is the finding of an inverse relationship between the receptors for oestrogen (ER) and epidermal growth factor (EGFR). The precise mechanisms responsible for this are poorly understood. Studies investigating the genes for these two receptors have suggested that their amplification or rearrangement is rare and are therefore unlikely to make a significant contribution to this relationship. In vitro studies have suggested that the two receptors are inversely modulated at transcription. However, no studies have examined the gene transcript and protein levels of both these receptors in clinical specimens of human breast cancer. The present study has addressed this issue. Specimens from 39 patients with primary human breast cancer were analysed using immunocytochemistry to quantify ER and EGFR levels and RNA slot blotting to quantify their respective gene transcript levels. Results derived from immunocytochemistry confirmed the presence of a significant inverse relationship. ER mRNA levels were found to be significantly correlated to ER whether measured as an index of staining or as the proportion of cells stained. Similarly, albeit to a lesser extent, EGFR mRNA correlated with EGFR whether measured as an index or as the proportion of cells stained. No significant linear inverse relationship was observed between gene transcripts of ER and EGFR. The reason was that of 27 cases containing EGFR mRNA only 15 also possessed EGFR, the other 12 (44.4%) containing no detectable EGFR. The level of EGFR mRNA in these two groups was comparable. Further analysis of these 27 cases revealed a significant association between ER positivity and a failure to detect EGFR protein. These data suggest that ER expression is determined by transcriptional modulation or altered transcript stability. This may also be the case for EGFR, but final expression may be further modified by other mechanisms, especially in ER positive cases. This raises the possibility that ER or the products of one of its upregulated genes may negatively modulate EGFR translation or decrease EGFR protein stability.