RT Journal Article
SR Electronic
T1 Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 056770
DO 10.1101/056770
A1 Jeffrey F. Hiken
A1 James I. McDonald
A1 Keith F. Decker
A1 Cesar Sanchez
A1 Jeremy Hoog
A1 Nathan D. VanderKraats
A1 Kyle L. Jung
A1 Margaret Akinhanmi
A1 Matthew J. Ellis
A1 John R. Edwards
YR 2016
UL http://biorxiv.org/content/early/2016/06/02/056770.abstract
AB Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.