Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes

Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ER beta) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ER beta mediates this effect. To investigate the functional role of intestinal ER beta during colitis-associated CRC we used intestine-specific ER beta knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNF alpha signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ER beta. Increased tumor formation in males and tumor size in females was noted upon intestinespecific ER beta knockout, accompanied by enhanced local expression of TNFa, deregulation of key NF kappa B targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ER beta protects against TNFa-induced damage intrinsically, and characterized an underlying genomewide signaling mechanism in CRC cell lines whereby ER beta binds to cis-regulatory chromatin areas of key NF kappa B regulators. Our results support a protective role of intestinal ER beta against colitis-associated CRC, proposing new therapeutic strategies.