Estrogen receptor β deficiency enhances small intestinal tumorigenesis in Apc^Min/+ 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 ApcMin/+ 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 (E2) 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−/−ApcMin/+ vs. ApcMin/+ female mice was confirmed by BrdU incorporation assay. Interestingly, functional categorization of microarray results revealed the TGFβ 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 TGFβ signaling pathway could contribute to the protective role of estrogens on intestinal tumorigenesis. © 2008 Wiley‐Liss, Inc.

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

“…1). In contrast, in the small intestine of the Min mouse, OVX reportedly increases adenomagenesis, perhaps owing to the loss of a suppressive estrogen effect (21,22). However, our analysis of the large dataset of Min mice from the McArdle Laboratory provided only marginally significant evidence for a 1.1-fold increased female susceptibility to adenoma development in the small intestine (Fig.…”

CARD9 Promotes Sex-Biased Colon Tumors in the APCmin Mouse Model

“…Other inflammation-related genes that have been examined in the APC min model either show no apparent sex specificity or show a female-specific effect (8,11,12). The male-specific effect in our study is somewhat surprising, but may have important clinical implications.…”

“…Interestingly, the inflammation profiles of the colonic and small-intestinal tumors from APC min mice are different, with the colonic tumors demonstrating more infiltrating immune cells and cytokine expression (7). Genetic evidence also suggests qualitative differences between APC min small-intestinal and colonic tumors (8,9). The APC min mouse has sex-specific phenotypes, whereby male APC min mice demonstrate higher multiplicity of colon tumors (10).…”

“…The APC min mouse has sex-specific phenotypes, whereby male APC min mice demonstrate higher multiplicity of colon tumors (10). Furthermore, several gene-ablation studies have demonstrated a femalespecific effect on adenoma formation (8,11,12).…”

Fibersol-2 induces apoptosis ofApc-deficient colorectal Cancer (SW480) cells and decreases polyp formation inApcMIN mice

“…21 Apc MIN/C mice present pathological differences in the small-intestinal and colonic regions 33,34 as well as female and male specific variances. [35][36][37] Thus, FS2s anti-tumor activity was studied in both male and female Apc MIN/C mice.…”