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Accession IconSRP066102

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer [RNA-seq]

Organism Icon Homo sapiens
Sample Icon 2 Downloadable Samples
Technology Badge IconIllumina Genome Analyzer IIx

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Description
Approximately 75% of breast cancers express estrogen receptor a (ERa) 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. Here we performed a genome-wide DNA methylation and expression analysis of cell line models to find epigenetically regulated genes involved in acquired aromatase inhibitor resistance. We discovered that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation and promotes phosphorylation and activation of ERa. Knockdown and inhibitor studies demonstrate that PTGER4 promotes AI resistance via ligand independent activation of the ERa-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/or treatments can improve AI resistant breast cancer treatment. Overall design: RNA-Seq was used to generate mRNA expression profiles of MCF7-LTED (long-term estrogen deprived) cells grown in charcoal stripped serum. Two replicates were performed.
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2
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