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

Topi, Geriolda LU ; Ranjan Satapathy, Shakti LU ; Dash, Pujarini LU ; Mehrabi, Syrina LU ; Ehrnström, Roy LU ; Olsson, Roger LU orcid ; Lydrup, Marie-Louise LU and Sjölander, Anita LU (2020) In Journal of Pathology 251(3). p.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,... (More)
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. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pathology
volume
251
issue
3
pages
13 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:32333795
  • scopus:85084587126
ISSN
0022-3417
DOI
10.1002/path.5453
language
English
LU publication?
yes
id
879f281a-f903-4928-9fff-fda6c6057e52
date added to LUP
2020-05-04 21:07:31
date last changed
2023-11-20 04:06:50
@article{879f281a-f903-4928-9fff-fda6c6057e52,
  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.}},
  author       = {{Topi, Geriolda and Ranjan Satapathy, Shakti and Dash, Pujarini and Mehrabi, Syrina and Ehrnström, Roy and Olsson, Roger and Lydrup, Marie-Louise and Sjölander, Anita}},
  issn         = {{0022-3417}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{297--309}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Tumour-suppressive effect of oestrogen receptor β in colorectal cancer patients, colon cancer cells, and a zebrafish model}},
  url          = {{http://dx.doi.org/10.1002/path.5453}},
  doi          = {{10.1002/path.5453}},
  volume       = {{251}},
  year         = {{2020}},
}