Abstract
The expression of the oestrogen receptor (ER) is one of the more important clinical parameters of breast cancer. However, the relationship between the ER and its ligand, oestradiol, and the enzymes that synthesise it are not well understood. The expression of mRNA transcripts of members of the oestradiol metabolic and signalling pathways including the ER was studied in detail. mRNA transcripts for aromatase (CYP19), 17-beta-hydroxysteroid dehydrogenase I, 17-beta-hydroxysteroid dehydrogenase II, ERalpha, ERbeta, steroid sulfatase (STS), oestradiol sulfotransferase (EST), cyclin D1 (CYCLD1) and ERBB2 were fluorometrically quantified by competitive RT-PCR using an internal standard in 155 breast carcinomas. In addition, the transcripts of CYP19 were analysed for alternative splicing/usage of exon 1 and an alternative poly A tail. A great variability of expression was observed, ranging from 0 to 2376 amol/mg RNA. The highest levels were observed for STS and EST, and the lowest levels (close to zero) were observed for the 17-beta-hydroxysteroid dehydrogenase isoenzymes. The levels of mRNA expression were analysed with respect to clinical and histopathological parameters as well as for disease-free survival. High correlation of the mRNA expression of STS, EST and 17-beta-hydroxysteroid dehydrogenase in the tumours suggested a common regulation, possibly by their common metabolite (oestradiol). Hierarchical clustering analysis in the 155 patients resulted in two main clusters, representing the ERalpha-negative and ERalpha-positive breast cancer cases. The mRNA expression of the oestradiol metabolising enzymes did not follow the expression of the ERalpha in all cases, leading to the formation of several subclasses of tumours. Patients with no expression of CYP19 and patients with high levels of expression of STS had significantly shorter disease-free survival time (P > 0.0005 and P < 0.03, respectively). Expression of ERbeta mRNA was a better prognostic factor than that of ERalpha in this material. Our results indicate the importance of CYP19 and the enzymes regulating the oestrone sulfate metabolism as factors of disease-free survival in breast cancer, in addition to the well-known factors ER and ERBB2.
Highlights
The expression of the oestrogen receptor (ER) is one of the more important clinical parameters of breast cancer
Our results indicate the importance of CYP19 and the enzymes regulating the oestrone sulfate metabolism as factors of disease-free survival in breast cancer, in addition to the well-known factors ER and ERBB2
We report a high-precision mRNA expression profile of the genes coding for the enzymes metabolising oestradiol, or coding for its most important receptors ERα and ERβ, as well as modifiers of hormonal response such as cyclin D1 and human epidermal receptor (HER)-2, coded by ERBB2 (Fig. 1, thick arrows) from the same tumours
Summary
The expression of the oestrogen receptor (ER) is one of the more important clinical parameters of breast cancer. Intratumoural mRNA expression of enzymes involved in the oestradiol metabolism has been studied in separate reports on different materials for single genes such as aromatase (CYP19) [4], steroid sulfatase (STS) [5] and 17-β-hydroxysteroid dehydrogenase I (HSD1) [6]. It is difficult, to see how these genes are expressed in concert. We attempt to quantify the mRNA expression of a number of genes in the oestradiol pathway (Fig. 1) simultaneously by fluorimetric quantitation of RT-PCR using gene-specific internal RNA standards
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