title: Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer.
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.
  
  
  OBJECTIVE
  To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer.
  
  
  METHODS
  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.
authors: Tytgat Institute for Liver & Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, , Amsterdam, The Netherlands.
authors: Jarom
authors: J
authors: Heijmans
authors: Mattheus C B
authors: MC
authors: Wielenga
authors: Sanne Liesbeth
authors: SL
authors: Rosekrans
authors: Jooske F
authors: JF
authors: van Lidth de Jeude
authors: Joris
authors: J
authors: Roelofs
authors: Patrick
authors: P
authors: Groothuis
authors: Antwan
authors: A
authors: Ederveen
authors: Eveline S M
authors: ES
authors: de Jonge-Muller
authors: Izak
authors: I
authors: Biemond
authors: James C H
authors: JC
authors: Hardwick
authors: Geert
authors: G
authors: D'Haens
authors: Daniel W
authors: DW
authors: Hommes
authors: Vanesa
authors: V
authors: Muncan
authors: Gijs R
authors: GR
authors: van den Brink
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D063646:Carcinogenesis / Q000139:chemically induced*; D003092:Colitis / Q000139:chemically induced*; D003110:Colonic Neoplasms / Q000139:chemically induced*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004958:Estradiol / Q000009:adverse effects*; D004967:Estrogens / Q000009:adverse effects*; D005260:Female; D020249:Hormone Replacement Therapy / Q000009:adverse effects; D007150:Immunohistochemistry; D008525:Medroxyprogesterone / Q000009:adverse effects*; D051379:Mice; D010052:Ovariectomy
chemical_list: D016207:Cytokines; D004967:Estrogens; D004958:Estradiol; D016264:Dextran Sulfate; D008525:Medroxyprogesterone; D001397:Azoxymethane
keywords: Cancer; Carcinogenesis; IBD Basic Research