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

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 ERRL alpha, ERR beta, and ERR gamma might be involved in the tumorigenesis of ovarian cancer. RT-PCR was performed to analyze the expression of hERR alpha, hERR beta, hERR beta-2, and hERR gamma 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 ERR alpha, a green fluorescent protein(GFP)reporter plasmid of hERRL alpha was constructed and transfected into the ovarian cancer cell line OVCAR-3. Expression of hERR(alpha-GFP fusion protein was observed in the nucleus of OVCAR-3 ovarian cancer cell lines. We observed increased expression of hERR alpha mRNA (T -0.020) and hERR gamma mRNA (P=0.045) in ovarian cancers compared to normal ovaries. In contrast, hERR beta was only observed in 9.1% of ovarian cancers. We found a positive correlation between the serum CA-125 levels and hERR alpha expression (P=0.012), but not hERR beta and hERR gamma expression. Survival analysis showed that the hERR alpha-positive group has a reduced overall survival (P-0.015), and the EPR gamma-positive group has a longer progression-free survival (P = 0.020). In multivariate analysis, expression of hERRa 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. hERR alpha may represent a biomarker of poor prognosis, and hERR gamma may be a new therapeutic target in ovarian cancer.