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Original article
Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer
  1. Jarom Heijmans1,
  2. Mattheus C B Wielenga1,
  3. Sanne Liesbeth Rosekrans1,
  4. Jooske F van Lidth de Jeude1,
  5. Joris Roelofs2,
  6. Patrick Groothuis3,
  7. Antwan Ederveen3,
  8. Eveline S M de Jonge-Muller4,
  9. Izak Biemond4,
  10. James C H Hardwick4,
  11. Geert D'Haens1,
  12. Daniel W Hommes4,5,
  13. Vanesa Muncan1,
  14. Gijs R van den Brink1
  1. 1Tytgat Institute for Liver & Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Merck, Sharpe and Dohme, Women's Health Department, Oss, The Netherlands
  4. 4Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Center for Inflammatory Bowel Diseases, University of California Los Angeles, Los Angeles, USA
  1. Correspondence to Jarom Heijmans, Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands; j.heijmans{at}amc.nl, Gijs R van den Brink, Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Meibergdreef 69-71,1105 BK Amsterdam, The Netherlands; g.r.vandenbrink{at}amc.nl

Abstract

Background Hormone replacement therapy increases the risk of developing ulcerative colitis in postmenopausal women. Chronic intestinal inflammation predisposes to colon cancer development, but effects of female hormones on colitis-associated cancer development have not been examined.

Aim To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer.

Design We performed ovariectomies, or sham operations, on mice, and supplemented these animals with indicated hormones. Additionally, we used oestrogen receptor α or β (Erα or Erβ) mutant mice. To study colitis or colitis-associated cancer, we used DSS only, or DSS and AOM, respectively.

Results Ovariectomy protects female mice against colitis-associated tumour development. Hormone replacement in ovariectomised mice with either oestradiol (E2), medroxyprogesterone acetate or a combination of both suggests that oestrogens are the ovary-derived factor that promotes tumour development in the context of inflammatory damage. E2-treated animals showed increased clinical symptoms and Il-6 production upon DSS-induced colitis and enhanced epithelial proliferation. Treatment with E2 markedly increased the numbers of polyps in ovariectomised mice and also strongly promoted tumour progression with all E2-treated animals developing at least one invasive adenocarcinoma, whereas, placebo-treated animals developed adenomas only. Using Er mutant mice, we find that the protumorigenic effect of oestrogen depends on both Erα and Erβ.

Conclusions Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.

  • Cancer
  • IBD Basic Research
  • Carcinogenesis

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