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Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors
1Prince Henry's Institute of Medical Research and the Monash University Department of Obstetrics and Gynecology, Monash Medical Center, Clayton, Victoria, Australia.
Abstract:
The factors involved in the pathogenesis of ovarian cancers remain unclear, and the response of these tumors to hormonal therapy is limited. The identification of a second estrogen receptor gene (ERbeta), expressed predominantly in ovarian granulosa cells, led us to explore its possible role in ovarian cancer, particularly in granulosa cell tumors (GCT). Several isoforms of ERbeta have been identified. We sought to define the patterns of both ERalpha and ERbeta gene expression in a panel of ovarian tumors consisting of GCT and serous and mucinous cystadenocarcinomas as well as in normal ovary. Expression was determined by RT-PCR using gene- and isoform-specific primers and probes combined with Southern blot analysis of the PCR products. Widespread expression of ERalpha was observed in all tumor types, but at relatively low levels. ERbeta is expressed predominantly in GCT, with lower levels in mucinous tumors and very low levels in serous tumors. The ERbeta2 splice variant previously reported in rodents was not observed. Only very low levels of the exon 5, exon 6, and exon 5/6 deletion variants were detected. The C-terminal truncation variant ERbeta(cx), however, exhibited widespread expression across all the tumor types. As ERbeta(cx) has been shown to be a ligand-independent antagonist of ERalpha action, the relative ratios of ERbeta(cx), ERalpha, and ERbeta may influence the response of a tumor to antiestrogen therapy.
Insights
Estrogen receptor beta (ERbeta) is predominantly expressed in ovarian granulosa cell tumors (GCT), unlike estrogen receptor alpha (ERalpha). This finding may impact antiestrogen therapy response in ovarian cancers.
Area of Science:
- Gynecologic Oncology
- Endocrinology
- Molecular Biology
Background:
- Ovarian cancer pathogenesis is not fully understood, and hormonal therapy response is limited.
- Estrogen receptor beta (ERbeta), a second estrogen receptor gene, is primarily found in ovarian granulosa cells, prompting investigation into its role in ovarian cancer, especially granulosa cell tumors (GCT).
Purpose of the Study:
- To determine the gene expression patterns of ERalpha and ERbeta in various ovarian tumors, including GCT, serous and mucinous cystadenocarcinomas, and normal ovarian tissue.
- To investigate the expression of ERbeta isoforms, specifically ERbeta2, deletion variants, and the ERbeta(cx) variant, in ovarian tumors.
Main Methods:
- Gene expression analysis using Reverse Transcription Polymerase Chain Reaction (RT-PCR) with specific primers and probes.
- Southern blot analysis of PCR products to quantify gene expression levels.
- Analysis of ERalpha, ERbeta, and ERbeta isoforms (ERbeta2, deletion variants, ERbeta(cx)) in normal ovary and ovarian tumor samples.
Main Results:
- Estrogen receptor alpha (ERalpha) showed widespread but low-level expression across all tested ovarian tumor types.
- Estrogen receptor beta (ERbeta) expression was predominant in GCT, with lower levels in mucinous and very low levels in serous cystadenocarcinomas.
- The ERbeta(cx) variant was widely expressed in all tumor types, while other ERbeta splice variants were detected at very low levels.
Conclusions:
- ERbeta is significantly expressed in GCT, suggesting a potential role in the pathogenesis of these tumors.
- The widespread expression of the ERbeta(cx) variant, a known antagonist of ERalpha, indicates its potential influence on tumor response to antiestrogen therapies.
- The relative expression levels of ERalpha, ERbeta, and ERbeta(cx) may be critical factors in predicting the efficacy of antiestrogen treatments for ovarian cancers.