Jun 2, 2016

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

BioRxiv : the Preprint Server for Biology
Jeff F HikenJohn R Edwards

Abstract

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. Additional...Continue Reading

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Mentioned in this Paper

Estrogen Biosynthetic Process
Prostaglandin Receptor
Genome-Wide Association Study
Study
DNA Methylation [PE]
CARM1
Gene Knockdown Techniques
Estrogen receptor alpha, human
Regulation of Biological Process
PTGER4 gene

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