| First Author | Hases L | Year | 2020 |
| Journal | Cancer Lett | Volume | 492 |
| Pages | 54-62 | PubMed ID | 32711097 |
| Mgi Jnum | J:296634 | Mgi Id | MGI:6467596 |
| Doi | 10.1016/j.canlet.2020.06.021 | Citation | Hases L, et al. (2020) Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes. Cancer Lett 492:54-62 |
| abstractText | Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERbeta) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERbeta mediates this effect. To investigate the functional role of intestinal ERbeta during colitis-associated CRC we used intestine-specific ERbeta 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 TNFalpha signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERbeta. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERbeta knockout, accompanied by enhanced local expression of TNFalpha, deregulation of key NFkappaB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERbeta protects against TNFalpha-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERbeta binds to cis-regulatory chromatin areas of key NFkappaB regulators. Our results support a protective role of intestinal ERbeta against colitis-associated CRC, proposing new therapeutic strategies. |
