Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

The estrogen receptor–binding fragment–associated antigen9 (EBAG9) has been identified as a primary estrogenresponsivegene in human breast cancer MCF7 cells. A highexpression of EBAG9 has been observed in invasive breastcancer and advanced prostate cancer, suggesting a tumorpromotingrole of the protein in malignancies. Here we showthat intratumoral (i.t.) administration of small interferingRNA against EBAG9 exerted overt regression of tumorsfollowing s.c. implantation of murine renal cell carcinoma(RCC) Renca cells. Overexpression of EBAG9 did not promotethe proliferation of culture Renca cells; however, theinoculated Renca cells harboring EBAG9 (Renca-EBAG9) inBALB/c mice grew faster and developed larger tumorscompared with Renca cells expressing vector alone (Rencavector).After renal subcapsular implantation, Renca-EBAG9tumors significantly enlarged compared with Renca-vectortumors in BALB/c mice, whereas both Renca-EBAG9 andRenca-vector tumors were developed with similar volumes inBALB/c nude mice. No apparent difference was observed inspecific cytotoxic T-cell responses against Renca-EBAG9 andRenca-vector cells; nonetheless, the number of infiltratingCD8+ T lymphocytes was decreased in Renca-EBAG9 subcapsulartumors. Furthermore, immunohistochemical study ofEBAG9 in 78 human RCC specimens showed that intense anddiffuse cytoplasmic immunostaining was observed in 87% ofthe cases and positive EBAG9 immunoreactivity was closelycorrelated with poor prognosis of the patients. Multivariateanalysis revealed that high EBAG9 expression was anindependent prognostic predictor for disease-specific survival(P = 0.0485). Our results suggest that EBAG9 is a crucialregulator of tumor progression and a potential prognosticmarker for RCC.