Estrogen receptor-β protects against colitis-associated neoplasia in mice

Estrogen receptor-beta (ERβ) has been suggested to exert anti-inflammatory and anti-tumorigenic effects in the colon, providing a translational potential to prevent and/or treat inflammatory bowel disease (IBD) and its progression to colitis-associated colorectal cancer (CAC). However, the specific direct role of ERβ in CAC has not yet been tested. We assessed the effects of ERβ deficiency in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model using ERβ knockout (βERKO) mice and wild-type (WT) littermates. These mice were injected with AOM followed by 1 week of DSS treatment, and sacrificed on weeks 9 or 16. βERKO mice developed more severe clinical colitis compared to WT mice, as evidenced by significantly higher disease activity index after DSS treatment, weight to length ratio of the colons, inflammation score and grade of dysplasia. ERβ-deficient colons presented greater number and size of polyps at weeks 9 and 16, respectively, and were characterized by a significant increase in interleukin (IL)-6, IL-17, tumor necrosis factor alpha and interferon-gamma mRNA levels. Furthermore, higher protein expression levels of nuclear factor-kappa B, inducible nitric oxide synthase, β-catenin, proliferating cell nuclear antigen, mucin-1 and significantly lower caveolin-1 and mucin-2 protein levels were shown in βERKO mice compared to WT mice. These data suggest a possible anti-inflammatory and anti-neoplastic mechanism of action of ERβ in CAC. These results demonstrate for the first time that ERβ provides protection in the AOM/DSS-induced CAC model in mice, suggesting a preventive and/or therapeutic potential for the use of ERβ-selective agonists in IBD.