Disruption of estrogen receptor signaling enhances intestinal neoplasia in Apc^Min/+ mice

Estrogen receptors (ERs) [ER α (Esr1) and ER β (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ER α and ER β is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ER α knockout and Apc^Min mouse strains, we demonstrate that ER α deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in Apc^Min/+ mice. Within the normal intestinal epithelium of Apc^Min/+ mice, ER α deficiency is associated with an accumulation of nuclear β-catenin, an indicator of activation of the Wnt-β-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ER α deficiency is associated with activation of Wnt - β-catenin signaling, ER α deficiency in the intestinal epithelium of Apc^Min/+ mice also correlated with increased expression of Wnt-β-catenin target genes. Through crosses between an ER β knockout and Apc^Min mouse strains, we observed some evidence that ER β deficiency is associated with an increased incidence of colon tumors in Apc^Min/+ mice. This effect of ER β deficiency does not involve modulation of Wnt-β-catenin signaling. Our studies suggest that ER α and ER β signaling modulate colorectal carcinogenesis, and ER α does so, at least in part, by regulating the activity of the Wnt - β-catenin pathway.