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Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

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Abstract

A subfamily of orphan receptors, estrogen receptor-related receptors (ERRs), has been demonstrated to modulate the transcription of some estrogen responsive genes via variant estrogen response elements (EREs). This study was conducted to determine whether human ERRα, ERRβ, and ERRγ might be involved in the tumorigenesis of ovarian cancer. RT-PCR was performed to analyze the expression of hERRα, hERRβ, hERRβ-2, and hERRγ mRNA in five ovarian cancer cell lines as well as 33 samples of ovarian cancer and 12 samples of normal ovary. Serum CA-125 levels were also analyzed in all samples by ELISA. Progression-free survival and overall survival of patients with different expression of ERRs were analyzed by the Kaplan–Meier method. To analyze the subcellular localization of ERRα, a green fluorescent protein (GFP)-reporter plasmid of hERRα was constructed and transfected into the ovarian cancer cell line OVCAR-3. Expression of hERRα-GFP fusion protein was observed in the nucleus of OVCAR-3 ovarian cancer cell lines. We observed increased expression of hERRα mRNA (P=0.020) and hERRγ mRNA (P=0.045) in ovarian cancers compared to normal ovaries. In contrast, hERRβ was only observed in 9.1% of ovarian cancers. We found a positive correlation between the serum CA-125 levels and hERRα expression (P=0.012), but not hERRβ and hERRγ expression. Survival analysis showed that the hERRα-positive group has a reduced overall survival (P=0.015), and the ERRγ-positive group has a longer progression-free survival (P=0.020). In multivariate analysis, expression of hERRα was an independent prognostic factor for poor survival (relative risk, 3.032; 95% CI, 1.27–6.06). Based on our results, ERRs may play an important role in ovarian cancer. hERRα may represent a biomarker of poor prognosis, and hERRγ may be a new therapeutic target in ovarian cancer.

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Acknowledgements

Pengming Sun was a scholarship holder of the Gottlieb–Daimler Benz Foundation (Serial No.17/05-03). This research was partly supported by the National Natural Science Foundation of China (Serial No. 30371477). We thank Prof. Jean Marc Vanacker for plasmids pSG-hERRα, pSG-mERRβ, pSG-mERRγ, and comments on the manuscript. We thank Dr. Eckardt Treuter for the GFP-reporter plasmid. We thank Dr. Michel R. Stallcup for the HA-tag-hERRγ plasmid. We thank Miss Cristina Pirvulescu for her excellent follow-up work. We also thank Dr. Wilko Weichert, Mrs. Elisabeth Glanz, and Mrs. Beate Pesche for their great support.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Peking University People’s Hospital, Peking University Health Science Center, Xizhimen South Street 11, 100044, Beijing, People’s Republic of China

    Pengming Sun & Lihui Wei

  2. Department of Obstetrics and Gynecology, Campus Virchow-Klinikum, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Pengming Sun, Jalid Sehouli, Alexander Mustea, Dominique Könsgen & Werner Lichtenegger

  3. Institute of Pathology, Campus Mitte, Charité Universitätsmedizin Berlin, Schumannstr. 20/21, 10117, Berlin, Germany

    Carsten Denkert & Ines Koch

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  1. Pengming Sun
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Correspondence to Jalid Sehouli.

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Sun, P., Sehouli, J., Denkert, C. et al. Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells. J Mol Med 83, 457–467 (2005). https://doi.org/10.1007/s00109-005-0639-3

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