Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Mary M. Heckler; Tizita Zewde Zeleke; Shailaja D. Divekar; Aileen I. Fernandez; Deanna M. Tiek; Jordan Woodrick; Alexander Farzanegan; Rabindra Roy; Aykut Üren; Susette C. Mueller; Rebecca B. Riggins

doi:10.18632/oncotarget.9719

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Research Papers:

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Mary M. Heckler, Tizita Zewde Zeleke, Shailaja D. Divekar, Aileen I. Fernandez, Deanna M. Tiek, Jordan Woodrick, Alexander Farzanegan, Rabindra Roy, Aykut Üren, Susette C. Mueller and Rebecca B. Riggins _

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Oncotarget. 2016; 7:47201-47220. https://doi.org/10.18632/oncotarget.9719

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Abstract

Mary M. Heckler1, Tizita Zewde Zeleke1, Shailaja D. Divekar1, Aileen I. Fernandez1, Deanna M. Tiek1, Jordan Woodrick1, Alexander Farzanegan1, Rabindra Roy1, Aykut Üren1, Susette C. Mueller1, Rebecca B. Riggins1

1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Correspondence to:

Rebecca B. Riggins, email: [email protected]

Keywords: ESRRB, ERRbeta, cell death, mitosis, p38 MAPK

Received: August 17, 2015 Accepted: May 19, 2016 Published: May 30, 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.

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Research Papers:

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Abstract