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Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Jul 26; Vol. 7 (30), pp. 47201-47220. - Publication Year :
- 2016
-
Abstract
- Breast cancer remains a leading cause of cancer-related death in women, and triple negative breast cancer (TNBC) lacks clinically actionable therapeutic targets. Death in mitosis is a tumor suppressive mechanism that occurs in cancer cells experiencing a defective M phase. The orphan estrogen-related receptor beta (ERRβ) is a key reprogramming factor in murine embryonic and induced pluripotent stem cells. In primates, ERRβ is alternatively spliced to produce several receptor isoforms. In cellular models of glioblastoma, short form (ERRβsf) and beta2 (ERRβ2) splice variants differentially regulate cell cycle progression in response to the synthetic agonist DY131, with ERRβ2 driving arrest in G2/M.The goals of the present study are to determine the cellular function(s) of ligand-activated ERRβ splice variants in breast cancer and evaluate the potential of DY131 to serve as an antimitotic agent, particularly in TNBC. DY131 inhibits growth in a diverse panel of breast cancer cell lines, causing cell death that involves the p38 stress kinase pathway and a bimodal cell cycle arrest. ERRβ2 facilitates the block in G2/M, and DY131 delays progression from prophase to anaphase. Finally, ERRβ2 localizes to centrosomes and DY131 causes mitotic spindle defects. Targeting ERRβ2 may therefore be a promising therapeutic strategy in breast cancer.<br />Competing Interests: The authors have no potential conflicts of interest to disclose.
- Subjects :
- Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Cycle Checkpoints drug effects
Cell Line, Tumor
DNA Damage
Female
Histones genetics
Histones metabolism
Humans
MAP Kinase Signaling System drug effects
MCF-7 Cells
Protein Isoforms
RNA Splicing
Receptors, Estrogen genetics
Transfection
Antimitotic Agents pharmacology
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Receptors, Estrogen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27363015
- Full Text :
- https://doi.org/10.18632/oncotarget.9719