Calcitriol induces estrogen receptor α expression through direct transcriptional regulation and epigenetic modifications in estrogen receptor-negative breast cancer cells.
Calcitriol
ER-negative breast cancer
ERα
VDR
epigenetic modulator
Journal
American journal of cancer research
ISSN: 2156-6976
Titre abrégé: Am J Cancer Res
Pays: United States
ID NLM: 101549944
Informations de publication
Date de publication:
2021
2021
Historique:
received:
30
07
2021
accepted:
11
11
2021
entrez:
12
1
2022
pubmed:
13
1
2022
medline:
13
1
2022
Statut:
epublish
Résumé
Patients with estrogen receptor (ER) α-negative breast tumors have a poor prognosis and are not suitable for hormone therapy. Previously, we demonstrated that calcitriol, the active metabolite of vitamin D, induces ERα expression and re-establishes the response to antiestrogens in ER-negative breast cancer cells. However, the mechanisms involved in this process have not been elucidated. Therefore, the present study was undertaken to investigate the mechanisms implicated in the calcitriol-induced ERα expression in ER-negative breast cancer cells. Using EMSA and ChIP assays, we found that the calcitriol/vitamin D receptor (VDR)/retinoic X receptor (RXR) complex binds to putative vitamin D response elements (VDREs) in the ERα gene promoter region. In addition, we established by a fluorometric assay that calcitriol decreased DNA-methyltransferase and histone deacetylase activities. Flow cytometry and qPCR analyses showed that co-treatment of calcitriol with inhibitors of the histone deacetylase and DNA methyltransferase, and genistein significantly increased ERα expression, compared to that observed with the compounds alone. In conclusion, the calcitriol-dependent ERα induction in ER-negative breast cancer cells results from binding of the VDR-RXR complex to VDREs in the ERα gene promoter region, including the downregulation of enzymes with chromatin-remodeling activities. These results may bring forth novel mechanistic knowledge into the actions of calcitriol in ERα-negative breast cancer.
Types de publication
Journal Article
Langues
eng
Pagination
5951-5964Informations de copyright
AJCR Copyright © 2021.
Déclaration de conflit d'intérêts
None.
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