Estrogen is known to have a protective effect in
colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in
azoxymethane (AOM)/
dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether
ovariectomy in a female AOM/DSS mouse model increases colorectal
tumorigenesis and whether
tumorigenesis is reduced by
estrogen supplementation after
ovariectomy. Clinical symptoms and histological severity of
colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2,
myeloperoxidase (MPO), and NF-κB-dependent
cytokines (
interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed.
Ovariectomy did not aggravate AOM/DSS-induced
colitis at 2 weeks. At weeks 10 and 16,
ovariectomy significantly increased
tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However,
ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of
colitis by decreasing the
protein and/or
mRNA levels of
estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing
estrogen receptor beta (ERβ) and nuclear Nrf2
protein expression and the
mRNA expression of related
antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous
estrogen in females protects against the development of proximal
colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced
colitis and
carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.