Estrogen receptor α or β loss in the colon of Min/+ mice promotes crypt expansion and impairs TGFβ and HNF3β signaling

Adenomatous polyposis coli (APC)-regulated Wnt and transforming growth factor- (TGF) signaling cooperate in the intestine to maintain normal enterocyte functions. Human clinical trials showed that estrogen [17-estradiol (E-2)], the ligand of nuclear receptors estrogen receptor (ER) and ER, inhibited colorectal cancer (CRC) in women. Consistent with this finding, we reported that E-2, ER and ER suppressed intestinal tumorigenesis in the C57BL/6J-Min/ (Min/) mouse, a CRC model. Here, we extended our results with further comparisons of colon and small intestine from intact female Apc(/) (WT), Min/ and ER-deficient Min/ mice. In the colon of ER-deficient Min/ mice, ER loss reduced TGF signaling in crypt base cells as evidenced by minimal expression of the effectors Smad 2, 3 and 4 in these strains. We also found reduced expression of Indian hedgehog (Ihh), bone morphogenetic protein 4 and hepatocyte nuclear factor 3 or FoxA2, factors needed for paracrine signaling between enterocytes and mesenchyme. In proximal colon, ER loss produced a > 10-fold increased incidence of crypt fission, a marker for wound healing and tumor promotion. These data, combined with our previous work detailing the specific roles of E-2, ER and ER in the colon, suggest that ER activity helps to maintain the intestinal stem cell (ISC) microenvironment by modulating epithelialstromal crosstalk in ways that regulate cytokine, Wnt and Ihh availability in the extracellular matrix (ECM).