Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ 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, Karen A. Gould

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Abstract

Estrogen receptors (ERs) [ER α (Esr1) and ER β (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ER α and ER β is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ER α knockout and ApcMin mouse strains, we demonstrate that ER α 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 α 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 α deficiency is associated with activation of Wnt - β-catenin signaling, ER α deficiency in the intestinal epithelium of ApcMin/+ mice also correlated with increased expression of Wnt-β-catenin target genes. Through crosses between an ER β knockout and ApcMin mouse strains, we observed some evidence that ER β deficiency is associated with an increased incidence of colon tumors in ApcMin/+ mice. This effect of ER β deficiency does not involve modulation of Wnt-β-catenin signaling. Our studies suggest that ER α and ER β signaling modulate colorectal carcinogenesis, and ER α does so, at least in part, by regulating the activity of the Wnt - β-catenin pathway.

Original languageEnglish (US)
Pages (from-to)1581-1590
Number of pages10
JournalCarcinogenesis
Volume30
Issue number9
DOIs
StatePublished - Sep 18 2009

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Cleveland, A. G., Oikarinen, S. I., Bynoté, K. K., Marttinen, M., Rafter, J. J., Gustafsson, J. Å., Roy, S. K., Pitot, H. C., Korach, K. S., Lubahn, D. B., Mutanen, M., & Gould, K. A. (2009). Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice. Carcinogenesis, 30(9), 1581-1590. https://doi.org/10.1093/carcin/bgp132