Tumour‐suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model

Oestrogen receptor beta (ERbeta) has been suggested to have anti-proliferative and anti-tumour effects in breast and prostate cancer cells, but other studies have indicated its tumour-promoting effects. Understanding the complex effects of this receptor in different contexts requires further study. We reported that high ERbeta expression is independently associated with improved prognosis in female colorectal cancer (CRC) patients. Herein, we investigated the possible anti-tumour effect of ERbeta and its selective agonist. CRC patients with high ERbeta expression had significantly higher levels of membrane-associated beta-catenin, cysteinyl leukotriene receptor 2 (CysLT2 R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which have anti-tumour effects, but lower levels of nuclear beta-catenin, cysteinyl leukotriene receptor 1 (CysLT1 R) and cyclooxygenase-2 (COX-2), which have tumour-promoting effects. These interesting findings were further supported by two different publicly available CRC mRNA datasets that showed a significant positive correlation between ERbeta expression and 15-PGDH and CysLT2 R expression and a negative correlation between ERbeta expression and beta-catenin, CysLT1 R and COX-2 expression. We next evaluated ERbeta expression in three different colon cancer mouse models; ERbeta expression was negatively correlated with tumorigenesis. Furthermore, treatment with the ERbeta-agonist ERB-041 reduced CysLT1 R, active beta-catenin and COX-2 levels but increased phospho-beta-catenin, CysLT2 R and 15-PGDH levels in HCT-116, Caco-2 and SW-480 colon cancer cells compared to vehicle-treated cells. Interestingly, ERB-041-treated cells showed significantly decreased migration, survival, and colonosphere formation and increased apoptotic activity, as indicated by increased CASPASE-3 and apoptotic blebs. Finally, patients with low ERbeta expression had significantly more distant metastasis at the time of diagnosis than patients with high ERbeta expression. Therefore, we studied the effects of ERB-041-treated colon cancer cells in a zebrafish xenograft model. We found significantly less distant metastasis of ERB-041-treated cells compared to vehicle-treated cells. These results further support ERbeta's anti-tumour role in colorectal cancer and the possible use of its agonist in CRC patients. This article is protected by copyright. All rights reserved.