PUBLICATION
Tumour-suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model
- Authors
- Topi, G., Satapathy, S.R., Dash, P., Fred Mehrabi, S., Ehrnström, R., Olsson, R., Lydrup, M.L., Sjölander, A.
- ID
- ZDB-PUB-200426-26
- Date
- 2020
- Source
- The Journal of pathology 251(3): 297-309 (Journal)
- Registered Authors
- Keywords
- CysLT1R, CysLT2R, ERbeta, colorectal cancer, metastasis
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis
- Caco-2 Cells
- Cell Movement*/drug effects
- Cell Proliferation*/drug effects
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism*
- Colorectal Neoplasms/pathology
- Estrogen Receptor beta/agonists
- Estrogen Receptor beta/genetics
- Estrogen Receptor beta/metabolism*
- Female
- Genes, APC
- HCT116 Cells
- HT29 Cells
- Humans
- Mice, Inbred C57BL
- Mice, Transgenic
- Neoplasm Metastasis
- Oxazoles/pharmacology
- Receptors, Leukotriene/genetics
- Receptors, Leukotriene/metabolism
- Signal Transduction
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 32333795 Full text @ J. Pathol.
Citation
Topi, G., Satapathy, S.R., Dash, P., Fred Mehrabi, S., Ehrnström, R., Olsson, R., Lydrup, M.L., Sjölander, A. (2020) Tumour-suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model. The Journal of pathology. 251(3):297-309.
Abstract
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 ERβ expression is independently associated with improved prognosis in female colorectal cancer (CRC) patients. Herein, we investigated the possible anti-tumour effect of ERβ and its selective agonist. CRC patients with high ERβ expression had significantly higher levels of membrane-associated β-catenin, cysteinyl leukotriene receptor 2 (CysLT2 R) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which have anti-tumour effects, but lower levels of nuclear β-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 ERβ expression and 15-PGDH and CysLT2 R expression and a negative correlation between ERβ expression and β-catenin, CysLT1 R and COX-2 expression. We next evaluated ERβ expression in three different colon cancer mouse models; ERβ expression was negatively correlated with tumorigenesis. Furthermore, treatment with the ERβ-agonist ERB-041 reduced CysLT1 R, active β-catenin and COX-2 levels but increased phospho-β-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 ERβ 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 ERβ'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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping