Chemopreventive effect of ERβ-Selective agonist on intestinal tumorigenesis in Apc(Min/+) mice

Mol Carcinog. 2011 May;50(5):359-69. doi: 10.1002/mc.20719. Epub 2010 Dec 28.

Abstract

Epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of colon cancer in postmenopausal women. Estrogen receptor beta (ERβ) is thought to be the principal mediator of the estrogen effect in the colon. Recent studies by our team suggested positive regulation of the transforming growth factor (TGF)β pathway by estrogen in mice colonocytes. We therefore wanted to investigate the effects of ERβ agonist treatment on intestinal tumorigenesis in Apc(Min/+) mice. Weaned Apc(Min/+) mice were injected subcutaneously three times a week for 12 wk with vehicle or ERβ-selective agonist, diarylpropionitrile (DPN, 5 mg/kg). DPN administration resulted in a significant reduction in small intestinal polyp multiplicity in both Apc(Min/+) male and female mice. Furthermore, the mean diameter of small intestinal polyps was lower in DPN-treated than vehicle-treated males, along with lower BrdU incorporation indices in jejunal and colon epithelial cells of both sexes. DPN treatment also increased apoptosis in colon epithelium as measured by TUNEL assay and cleaved caspase 3 quantification. The effect of DPN on various components of the TGFβ pathway was also studied in colonocytes. DPN treatment increased expression of TGFβ1 and TGFβ3 transcripts, levels of nuclear and phosphorylated Smad2 as well as p27 cell-cycle inhibitor, a TGFβ pathway target gene. Our results demonstrate that DPN treatment reduces intestinal tumorigenesis in Apc(Min/+) mice. Furthermore, we suggest that positive regulation of the TGFβ pathway by ERβ activation could contribute to the protective role of estrogen in intestinal tumor development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics*
  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Caspase 3 / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Epithelium / pathology
  • Estrogen Receptor beta / agonists*
  • Female
  • Gene Expression / drug effects
  • In Situ Nick-End Labeling
  • Injections, Subcutaneous
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / pathology
  • Intestinal Neoplasms / prevention & control*
  • Intestinal Polyps / genetics
  • Intestinal Polyps / pathology
  • Intestinal Polyps / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nitriles / administration & dosage
  • Nitriles / pharmacology*
  • Phosphorylation / drug effects
  • Propionates / administration & dosage
  • Propionates / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / genetics

Substances

  • Adenomatous Polyposis Coli Protein
  • Estrogen Receptor beta
  • Nitriles
  • Propionates
  • Smad2 Protein
  • Transforming Growth Factor beta
  • diarylpropionitrile
  • Caspase 3