TY - JOUR
T1 - Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer
AU - Heijmans, Jarom
AU - Wielenga, Mattheus C. B.
AU - Rosekrans, Sanne Liesbeth
AU - van Lidth de Jeude, Jooske F.
AU - Roelofs, Joris
AU - Groothuis, Patrick
AU - Ederveen, Antwan
AU - de Jonge-Muller, Eveline S. M.
AU - Biemond, Izak
AU - Hardwick, James C. H.
AU - D'Haens, Geert
AU - Hommes, Daniel W.
AU - Muncan, Vanesa
AU - van den Brink, Gijs R.
PY - 2014
Y1 - 2014
N2 - 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. To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. 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. 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. Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage
AB - 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. To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. 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. 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. Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage
U2 - https://doi.org/10.1136/gutjnl-2012-304216
DO - https://doi.org/10.1136/gutjnl-2012-304216
M3 - Article
C2 - 23408349
SN - 0017-5749
VL - 63
SP - 310
EP - 316
JO - Gut
JF - Gut
IS - 2
ER -