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

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 (ERR beta) is a key reprogramming factor in murine embryonic and induced pluripotent stem cells. In primates, ERR beta is alternatively spliced to produce several receptor isoforms. In cellular models of glioblastoma, short form (ERR beta sf) and beta2 (ERR beta 2) splice variants differentially regulate cell cycle progression in response to the synthetic agonist DY131, with ERR beta 2 driving arrest in G2/M. The goals of the present study are to determine the cellular function(s) of ligand activated ERR beta 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. ERR beta 2 facilitates the block in G2/M, and DY131 delays progression from prophase to anaphase. Finally, ERR beta 2 localizes to centrosomes and DY131 causes mitotic spindle defects. Targeting ERR beta 2 may therefore be a promising therapeutic strategy in breast cancer.