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

Abstract

Clinical evidence suggests that estradiol replacement therapy reduces colon cancer risk in 'post'menopausal women. In colon epithelial cells, the estrogen receptor β (ERβ) 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 ERβ deficiency on intestinal tumorigenesis in the ApcMinl+ 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. ERβ-/- mice, treated with estradiol (E 2) or vehicle. Specifically in female, ERβ deficiency was found to be associated with higher adenoma multiplicity in the small intestine, but not in the colon. Furthermore, tumors from ERβ-/-Apcmin/+ female mice were on average significantly larger than those from control ApcMin/+ mice. Higher steady-state proliferation in epithelial cells of the jejunum and colon from ERβ-/- Apc Min/+ vs. ApcMin/+ female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGFß signaling pathway to be modulated in colonocytes, especially for the WT + E2 vs. WT + Vehicle and the ERβ-/- + E2 vs. WT + E2 comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGFβ pathway to be upregulated in colonocytes from E2-treated WT and ERβ-/- mice and downregulated in ERβ-deficient mice, mostly in an E2-independent manner. Therefore, our results demonstrate that ERβ deficiency enhances small intestinal tumorigenesis and suggest that modulation of the TGF- signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis. © 2008 Wiley-Liss, Inc.