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Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer

Jarom Heijmans, Mattheus C B Wielenga, Sanne Liesbeth Rosekrans, Jooske F van Lidth de Jeude, Joris Roelofs, Patrick Groothuis, Antwan Ederveen, Eveline S M de Jonge-Muller, Izak Biemond, James C H Hardwick, Geert D'Haens, Daniel W Hommes, Vanesa Muncan, Gijs R van den Brink
Gut 2014, 63 (2): 310-6

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.


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