Tumour-suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model
Menée à l'aide de trois modèles murins de cancer du côlon, de cellules coliques, d'une xénogreffe sur un modèle de poisson-zèbre et d'échantillons tumoraux de patients atteints d'un cancer colorectal, cette étude met en évidence le rôle du récepteur des estrogènes
Oestrogen receptor
β (ERβ) 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 ER
β expression is independently associated with improved prognosis in female colorectal cancer (CRC) patients. Herein, we investigated the possible anti
‐tumour effect of ER
β and its selective agonist. CRC patients with high ERβ expression had significantly higher levels of membrane
‐associated
β
‐catenin, cysteinyl leukotriene receptor 2 (CysLT2R) and 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH), which have anti‐tumour effects, but lower levels of nuclear
β
‐catenin, cysteinyl leukotriene receptor 1 (CysLT1R) 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 ER
β expression and 15
‐PGDH and CysLT2R expression and a negative correlation between ER
β expression and β
‐catenin, CysLT1R and COX‐2 expression. We next evaluated ER
β expression in three different colon cancer mouse models; ERβ expression was negatively correlated with tumorigenesis. Furthermore, treatment with the ERβ
‐agonist ERB‐041 reduced CysLT1R, active
β
‐catenin and COX‐2 levels but increased phospho‐
β
‐catenin, CysLT2R 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 ER
β expression had significantly more distant metastasis at the time of diagnosis than patients with high ERβ 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 ER
β’s anti
‐tumour role in colorectal cancer and the possible use of its agonist in CRC patients.