Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro

Schüler-Toprak, Susanne; Haring, John H.; Inwald, Elisabeth C.; Moehle, Christoph; Ortmann, O.; Treeck, Oliver

doi:10.1186/s12885-016-2973-y

Cited by 53 publications

(55 citation statements)

References 61 publications

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“…Since there is no ERα expressed in triple-negative breast cancer (TNBC), it is not yet known what the target of ERβ is, nor is it known whether ERβ is a driver of cancer in TNBC. In vitro studies with TNBC cell lines have shown that ERβ prevents invasiveness but does not affect proliferation (38)(39)(40). Studies with TNBC cell lines showed that ERβ can affect invasiveness by secretion of cystatins (41) and can increase innate immunity (42).…”

Section: Discussionmentioning

confidence: 99%

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Warner

Montanholi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβOS−/−]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβcrispr−/−mice was similar to, but more severe than, that in the ERβOS−/−mice. In the VP of 6-mo-old ERβcrispr−/−mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURα, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor α and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERβ is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERα, respectively.

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Section: Discussionmentioning

confidence: 99%

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Warner

Montanholi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…ERB-041 is a potent, selective ERβ agonist and has been tested in phase 2 clinical trial for treatment of rheumatoid arthritis [ 16 ]. ERB-041 has been found to suppress UVB-induced skin cancer in a mouse model [ 17 ] and inhibit invasion of triple-negative breast cancer cells in vitro [ 18 ]. A recent finding revealed inhibition of ovarian cancer cell proliferation by ERB-041 [ 19 ], but overall studies of ERB-041 on ovarian cancer were very limited.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer

et al. 2018

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BackgroundOvarian cancer is the most lethal gynaecological malignancy. Chemotherapy is the main stay of treatment for metastatic disease, with modest response rates but significant side effects. Therefore, there is a need for alternative therapies that can control the disease while offering good quality of life. Ovarian cancer cells express both estrogen receptor subtypes (ERα and ERβ). There is growing evidence that ERβ is anti-oncogenic. Genistein and daidzein are phytoestrogens found in soybeans and they display higher affinity to bind ERβ. ERB-041 is a potent selective ERβ agonist. In this study, we aimed to investigate the effects of genistein, daidzein and ERB-041 on ovarian cancer.MethodsOvarian cancer cell lines were treated with genistein, daidzein and ERB-041 in pharmacological doses. Cell migration, invasion, proliferation, cell cycle arrest, apoptosis and sphere formation were assessed by Transwell migration and invasion assays, XTT assay, focus formation, flow cytometry and sphere formation assay, respectively. Immunoblotting analysis was performed to determine the downstream signaling pathways.ResultsWe found that genistein, daidzein and ERB-041 significantly inhibited ovarian cancer cell migration, invasion, proliferation, as well as induced cell cycle arrest and apoptosis. Significantly inhibitory effect on the size and number of sphere formed in genistein, daidzein and ERB-041 treated cells was also demonstrated. Moreover, genistein, daidzein and ERB-041 treatment reduced p-FAK, p-PI3K, p-AKT, p-GSK3β, p21 or cyclin D1 expression in ovarian cancer cells.ConclusionGenistein, daidzein and ERB-041 decreased ovarian cancer cell migration, invasion, proliferation and sphere formation, and induced cell cycle arrest and apoptosis with altered FAK and PI3K/AKT/GSK signaling and p21/cyclin D1 expression, suggesting their roles on ovarian cancer cell metastasis, tumorigenesis and stem-like properties and their potential as alternative therapies for ovarian cancer patients.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0559-2) contains supplementary material, which is available to authorized users.

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“…The classical ERs are most evaluated in breast cancer, where their presence plays a significant role in choosing the best treatment regimen . Several functional data on ERα and ERβ have been obtained, and in triple‐negative breast cancer cell lines ERβ activation by agonists inhibited the invasiveness of the cancer cells in vitro . In prostate cancer, ERα promotes metastasis, while ERβ has an antiproliferative effect .…”

Section: Discussionmentioning

confidence: 99%

“…38 Several functional data on ERa and ERb have been obtained, and in triple-negative breast cancer cell lines ERb activation by agonists inhibited the invasiveness of the cancer cells in vitro. 39 In prostate cancer, ERa promotes metastasis, while ERb has an antiproliferative effect. 30,40 In ovarian cancer, ERb positivity was associated with poor overall survival (OS) and patients with cytoplasmic ERb2 splice variant positivity showed chemoresistance and worse disease outcome.…”

Section: Discussionmentioning

confidence: 99%

Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

Fábián

Rencz

Krenács

et al. 2017

Acad Dermatol Venereol

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Agonists and knockdown of estrogen receptor β differentially affect invasion of triple-negative breast cancer cells in vitro

Cited by 53 publications

References 61 publications

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer

Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

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