Journal Article

Disruption of estrogen receptor signaling enhances intestinal neoplasia in <i>Apc<sup>Min/+</sup></i> mice

Alicia G. Cleveland, Seija I. Oikarinen, Kimberly K. Bynoté, Maija Marttinen, Joseph J. Rafter, Jan-Åke Gustafsson, Shyamal K. Roy, Henry C. Pitot, Kenneth S. Korach, Dennis B. Lubahn, Marja Mutanen and Karen A. Gould

in Carcinogenesis

Volume 30, issue 9, pages 1581-1590
Published in print September 2009 | ISSN: 0143-3334
Published online June 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp132
Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice

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Estrogen receptors (ERs) [ERα (Esr1) and ERβ (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ERα and ERβ is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ERα knockout and ApcMin mouse strains, we demonstrate that ERα 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, ERα 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 ERα deficiency is associated with activation of Wnt–β-catenin signaling, ERα 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 ERα and ERβ signaling modulate colorectal carcinogenesis, and ERα does so, at least in part, by regulating the activity of the Wnt–β-catenin pathway.

Journal Article.  6796 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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