Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation

Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with [beta]-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the [Apc.sup.Min/+] mice, a genetic model of intestinal cancer. Likewise, [Lrh-1.sup.+/-] mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-[alpha] Reciprocally, decreased LRH-1 expression in [Lrh-1.sup.+/-] mice attenuates TNF-[alpha] expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways. [beta]-catenin | colon cancer | nuclear receptors