Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice

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