Abstract 2045: Intriguing role of estrogen-related receptor alpha (ERRα) in colorectal cancer

Abstract

Abstract Besides its well-known function in energetic metabolism, the nuclear receptor Estrogen-Related Receptor Alpha (ERRα) has also been shown to be overexpressed in breast, ovarian, uterine, prostate and colon cancer and to be associated to a poor prognosis in some of these cancer types. Interestingly, an ERRα splice variant mainly expressed in non cancerous tissues has been reported. This variant missing the fifth exon (ERRα Δ5) is still expected to interact with DNA and form dimers but cannot recruit coactivators, therefore being devoid of any transcriptional activity. AIM: Determine the role of ERRα as well as ERRα Δ5 in intestinal tumorigenesis. METHODS: shRNA-mediated silencing of ERRα and overexpression of ERRα Δ5 were performed by lentivirus infection in DLD1 and HCT116 human colon cancer cells. The interaction between both proteins was investigated as well as their respective roles in various tumorigenic processes. RESULTS: Silencing of ERRα by shRNA reduced proliferation of DLD1 and HCT116 cells as measured by growth kinetics and anchorage-independent growth assays in soft agar. We also observed that ERRα knockdown cells grew into smaller tumors when subcutaneously implanted in NUDE mice. Furthermore, FACS-scan analysis revealed that ERRα silencing delays G1 to S phase transition in colon cancer cells. Differential expression of a splice variant of ERRα (ERRα Δ5) in cancer vs normal tissues would support the importance of ERRα role in colorectal carcinogenesis. This is the case at least for colon tumors as cancerous samples display lower amount of ERRα Δ5 and higher amount of ERRα compared to adjacent paired normal tissues, as measured by Western Blot analysis. Interaction between both variants has been characterized by immunoprecipitation assays, confirming the conserved dimerization potential of ERRα Δ5 variant with the full length ERRα. Furthermore, luciferase assays revealed that ERRα Δ5 is transcriptionaly inactive and its expression inhibits the transcriptional activity of ERRα on its target genes, suggesting that this variant acts as a dominant negative for ERRα. Interestingly, the reintroduction of ERRα Δ5 in human colon cancer cells leads to the reduction of cell growth and soft agar colony formation. CONCLUSION: Strong ERRα expression is associated with cancerous tissues and is required for the intense proliferation of colon cancer cells. Interestingly, the poorly active splice variant ERRα Δ5 is lost in cancerous colon tissues and has antiproliferative properties when reintroduced in colon cancer cells. Since this splice variant could interact with ERRα and inhibit its activity, ERRα Δ5 reduction of expression in cancerous tissue could allow ERRα to fully promote colon cancer cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2045. doi:10.1158/1538-7445.AM2011-2045