Abstract 5032: High ERbeta expression correlates with the tumor suppressor 15-PGDH and PGD2 synthase in a female cohort of colorectal cancer patients
Authors: Topi Geriolda , Dash Pujarini , Satapathy Shakti R. , Mehrabi Syrina , Ehrnström Roy , Lydrup Marie-Louise , Sjölander Anita 
Published: August 2019

Background: The estrogen receptor β (ERβ) is the predominant ER in the colon mucosa. We have previously reported that high expression of ERβ is independently associated with a better prognosis in female patient with colorectal cancer (CRC). β-catenin and cyclooxygenase-2 (COX-2) are well known to be involved in CRC tumorigenesis. We have shown that a high level of CysLT2R, a low level of CysLT1R and high mast cell density are correlated with good prognosis in CRC patients. β-catenin and some inflammatory mediators, such are cyclooxygenase-2 (COX-2), cysteinyl leukotriene receptor 1 and 2 (CysLT1R, CysLT2R), prostaglandin D2 (PGD2), 15-PGDH activity and mast cells have been associated with CRC. Aim: To investigate the association between ERβ and other tumor modulators in CRC patients, as well as the underlying mechanism in colon cancer cell lines.

Material and methods: A tissue microarray of primary CRCs from 320 female patients was stained for the expression of ERβ, COX-2, 15-PGDH, CysLT1R, CysLT2R, ß-catenin, PGD synthase and mast cells. The Immunohistochemistry technique was used to evaluate the staining intensity, which was assigned an Immuno-Reactive Score (IRS). The zebrafish xenograft model was used to study colon cancer cells metastasis. ERβ -041 (an ERβ agonist) was injected into the zebrafish perivitelline space to allow for xamination of its effect on colon cancer cells. After 48 h, the tail, considered the distant metastatic site, was investigated for the presence of the metastasized cells. The effect of ERβ on colon cancer cells (SW-480 and HCT-116) after treatment with ERβ-041 was studied by wound healing and trans-well migration assay, as well as by survival assay.

Results: Patients with high ERβ expression had significantly higher levels of membrane ß-catenin, CysLT2R, 15-PGDH and PGD synthase, which all are known to have an anti-tumor effect. These patients had significantly lower levels of CysLT1R, COX-2 and nuclear ß-catenin expression, which are known to have pro-tumorigenic effects. In addition, patients with high ERβ expression had higher numbers of mast cells, which are a major source of PGD2 synthase and PGD2. In the zebrafish xenograft model, the ERB-041 treated cells showed no distant metastasis, unlike the untreated cells. ERβ stimulation of colon cancer cells produced a significant decrease in migration and survival compared to that of the untreated control cells after 48 h post-stimulation.

Conclusion: High ERβ expression was significantly correlated with anti-tumorigenic inflammatory mediators and lower nuclear ß-catenin in patients with CRC. These results strengthen our hypothesis regarding the beneficial role of ERβ in CRC patients. Our results raise the possibility of cross-talk between ERβ, CysLT1R and CysLT2R signalling.

Citation Format: Geriolda Topi, Pujarini Dash, Shakti R. Satapathy, Syrina Mehrabi, Roy Ehrnström, Marie-Louise Lydrup, Anita Sjölander. High ERbeta expression correlates with the tumor suppressor 15-PGDH and PGD2 synthase in a female cohort of colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5032.