Carcinogenesis Advance Access originally published online on June 11, 2009
Carcinogenesis 2009 30(9):1581-1590; doi:10.1093/carcin/bgp132
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Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
1 Department of Applied Chemistry and Microbiology (Nutrition), PO Box 66, University of Helsinki, Helsinki FIN-00014, Finland
2 Department of BioSciences and Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden
3 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
4 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
5 McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA
6 Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
7 Department of Biochemistry
8 Department of Child Health
9 Department of Animal Sciences
10 MU Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia, MO, USA
* To whom correspondence should be addressed. Tel: +1 402 559 2456; Fax: +1 402 559 7328; Email: kagould{at}unmc.edu
Estrogen receptors (ERs) [ER
(Esr1) and ERβ (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ER and ERβ is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ER knockout and ApcMin mouse strains, we demonstrate that ER deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in ApcMin/+ mice. Within the normal intestinal epithelium of ApcMin/+ mice, ER deficiency is associated with an accumulation of nuclear β-catenin, an indicator of activation of the Wnt–β-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ER deficiency is associated with activation of Wnt–β-catenin signaling, ER deficiency in the intestinal epithelium of ApcMin/+ mice also correlated with increased expression of Wnt–β-catenin target genes. Through crosses between an ERβ knockout and ApcMin mouse strains, we observed some evidence that ERβ deficiency is associated with an increased incidence of colon tumors in ApcMin/+ mice. This effect of ERβ deficiency does not involve modulation of Wnt–β-catenin signaling. Our studies suggest that ER and ERβ signaling modulate colorectal carcinogenesis, and ER does so, at least in part, by regulating the activity of the Wnt–β-catenin pathway.
Abbreviations: Apc, adenomatous polyposis coli; ER, estrogen receptor; E2, 17β-estradiol; Min, multiple intestinal neoplasia; PCR, polymerase chain reaction
These authors contributed equally to this work. Received November 6, 2008; revised April 30, 2009; accepted May 23, 2009.