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Updated: Mar 18, 2026
Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
Published on: February 21, 2014
Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer
Mary M Heckler1, Tizita Zewde Zeleke1, Shailaja D Divekar1
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
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.
Insights
Triple negative breast cancer (TNBC) has limited treatment options. The study shows targeting the ERRβ2 receptor with DY131 may offer a new therapeutic strategy by inducing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to a lack of targeted therapies.
- Mitotic cell death is a crucial tumor suppressive mechanism.
- Estrogen-related receptor beta (ERRβ) splice variants, including ERRβ2, play roles in cell cycle regulation.
Purpose of the Study:
- To investigate the function of ERRβ splice variants in breast cancer.
- To evaluate the synthetic agonist DY131 as a potential antimitotic agent for TNBC.
Main Methods:
- Utilized breast cancer cell line models.
- Administered the synthetic agonist DY131.
- Analyzed cell cycle progression, cell death pathways (p38 kinase), and mitotic spindle integrity.
- Investigated ERRβ2 localization.
Main Results:
- DY131 inhibited growth across various breast cancer cell lines, inducing cell death via the p38 stress kinase pathway.
- A bimodal cell cycle arrest was observed, with ERRβ2 specifically mediating G2/M arrest.
- DY131 treatment delayed prophase to anaphase progression and caused mitotic spindle defects.
- ERRβ2 was found to localize to centrosomes.
Conclusions:
- Ligand-activated ERRβ variants, particularly ERRβ2, influence breast cancer cell proliferation and cell cycle progression.
- DY131 demonstrates antimitotic potential by inducing mitotic defects and cell death.
- Targeting ERRβ2 represents a promising therapeutic strategy for breast cancer, especially TNBC.
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