Carcinogenesis Advance Access published online on June 11, 2009
Carcinogenesis, doi:10.1093/carcin/bgp132
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Disruption of Estrogen Receptor Signaling Enhances Intestinal Neoplasia in ApcMin/+ Mice
1 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
2 Department of Applied Chemistry and Microbiology (Nutrition), P.O. Box 66, FIN-00014 University of Helsinki, Finland
3 Department of BioSciences and Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden, and Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204
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, NIH, Research Triangle Park, North Carolina, USA
7 Department of Biochemistry, University of Missouri, Columbia, MO, USA
8 Department of Child Health, University of Missouri, Columbia, MO, USA
9 Department of Animal Sciences, University of Missouri, Columbia, MO, USA
10 MU Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia, MO, USA
Address correspondence to: Karen A. Gould: Phone: (402) 559-2456, Fax: (402) 559-7328, E-mail: kagould{at}unmc.edu
Estrogen Receptors 
(ER or ESR1) and β (ERβ or 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 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.
Key Words: estrogen receptor • tumorigenesis • intestine • Apc • colon
* These authors contributed equally to this work
Received November 6, 2008; revised April 30, 2009; accepted May 23, 2009.