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Estrogen receptor β deficiency enhances small intestinal tumorigenesis in Apc Min/+ mice
Author(s) -
Giroux Véronique,
Lemay Frédéric,
Bernatchez Gérald,
Robitaille Yolaine,
Carrier Julie C.
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23532
Subject(s) - estrogen receptor , carcinogenesis , medicine , endocrinology , estrogen , estrogen receptor alpha , downregulation and upregulation , biology , colorectal cancer , pathogenesis , cancer research , cancer , gene , breast cancer , biochemistry
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 Apc Min/+ 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 β −/− 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 ER β −/− 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 β −/− Apc Min/+ vs. Apc Min/+ 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 + E 2 vs. WT + Vehicle and the ER β −/− + E 2 vs. WT + E 2 comparisons. Using quantitative PCR analysis, we observed transcripts from ligands of the TGFβ pathway to be upregulated in colonocytes from E 2 ‐treated WT and ER β −/− mice and downregulated in ERβ‐deficient mice, mostly in an E 2 ‐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.