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

Autor: Keith F. Decker, Margaret Akinhanmi, Kyle L. Jung, Jeremy Hoog, César Sánchez, Nathan D. VanderKraats, James I. McDonald, John R. Edwards, Jeffrey F. Hiken, Lisa E. Rois, Matthew J. Ellis
Rok vydání: 2016
Předmět:
0301 basic medicine
Protein-Arginine N-Methyltransferases
Cancer Research
medicine.medical_specialty
Estrogen receptor
Antineoplastic Agents
Breast Neoplasms
Biology
Molecular oncology
Article
Epigenesis
Genetic
Epigenome
03 medical and health sciences
Breast cancer
Growth factor receptor
Internal medicine
Breast Cancer
Genetics
medicine
Humans
Epigenetics
Prostaglandin Receptor
skin and connective tissue diseases
Prostaglandin receptor
Molecular Biology
Cell Proliferation
EP4
Aromatase Inhibitors
Estrogen Receptor alpha
Endocrine Therapy
Cancer
DNA
Neoplasm
DNA Methylation
Cell cycle
medicine.disease
3. Good health
Gene Expression Regulation
Neoplastic
030104 developmental biology
Endocrinology
Drug Resistance
Neoplasm
MCF-7 Cells
Cancer research
Female
lipids (amino acids
peptides
and proteins)
Receptors
Prostaglandin E
EP4 Subtype
Signal Transduction
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
DOI: 10.1038/onc.2016.397
Popis: 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. Our exploratory 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.
Databáze: OpenAIRE
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