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

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

doi:10.18632/oncotarget.9719

Mary M Heckler, Aileen I Fernandez + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.9719

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Journal: Oncotarget	Publication Date: May 30, 2016
Citations: 15	License type: cc-by

Affiliation: Georgetown University Medical Center

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.

Highlights

Breast cancer remains a leading cause of cancerrelated death in women [1, 2]
We recently published that ERRβsf has constitutive and ligand-modulated activity on the p21 promoter in cellular models of glioblastoma (GBM, [27]) but that ERRβ2 cannot activate the p21 promoter-reporter
We measured the activity of these exogenous splice variants on estrogen response elements (EREs)- and estrogenrelated response element (ERRE)-luciferase heterologous promoter-reporter constructs in breast cancer cells

Summary

Introduction

Breast cancer remains a leading cause of cancerrelated death in women [1, 2]. The prognosis for patients with hormone receptor-positive and/or human epidermal growth factor receptor 2 (HER2)-positive disease has been significantly improved by antiestrogen and/or anti-HER2 therapies. Death in mitosis (DiM), is a tumor suppressive mechanism that occurs in cancer cells experiencing a defective M phase, leading to apoptosis or other forms of cell death [5, 6]. An incomplete mitotic block allows slippage into the G1 phase where, in the presence of apoptotic defects that may prevent elimination of these cells, chromosomal instability can lead to more aggressive tumor behavior. Other approaches include the inhibition of centrosome clustering, a mechanism to complete bipolar division used by cancer cells with centrosomal amplification; small molecules which inhibit this process are being www.impactjournals.com/oncotarget developed as novel antimitotic therapies in breast and other cancers [8,9,10,11]. MYC-mediated modulation of pro-apoptotic BH3-only proteins has recently been implicated in the control of DiM [12]

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