Estrogen receptor β deficiency enhances small intestinal tumorigenesis in ApcMin/+ mice

Clinical evidence suggests that estradiol replacement therapy reduces colon cancer risk in 'post'menopausal women. In colon epithelial cells, the estrogen receptor beta (ER beta) is the predominant ER subtype and is thought to mediate the genomic effect of estrogens. The first aim of this study was to investigate the consequence of ER beta deficiency on intestinal tumorigenesis in the Ape mouse model. Furthermore, to explore the biological mechanisms by which estrogens may influence the pathogenesis of colorectal cancer, we performed gene expression profiles in colonocytes from ovariectomized wild-type (WT) vs. ER beta(-/-) mice, treated with estradiol (E(2)) or vehicle. Specifically in female, ER beta deficiency was found to be associated with higher adenoma multiplicity in the small intestine, but not in the colon. Furthermore, tumors from ER beta(-/-) Apc(Min/+) female mice were on average significantly larger than those from control Apc(Min/+) mice. Higher steady-state proliferation in epithelial cells of the jejunum and colon from ER beta(-/-)Apc(Min/+) vs. Ape(Min/+) female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGF beta signaling pathway to be modulated in colonocytes, especially for the WT + E(2) VS. WT + Vehicle and the ER beta(-/-) + E(2) VS. WT + E(2) comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGF beta pathway to be upregulated in colonocytes from E(2)-treated WT and ER beta(-/-) mice and downregulated in ER beta-deficient mice, mostly in an E(2)-independent manner. Therefore, our results demonstrate that ER beta deficiency enhances small intestinal tumorigenesis and suggest that modulation of the TGF beta signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis. (C) 2008 Wiley-Liss, Inc.