title: Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer.
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 ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation 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 AI resistance indicated that prostaglandin E2receptor 4 (PTGER4) is upregulated 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. In addition, 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.
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Hiken
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: McDonald
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Decker
authors.affiliation: Haematology-Oncology Department, Cancer Programme, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: VanderKraats
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Jung
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Akinhanmi
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Rois
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Edwards
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D049109:Cell Proliferation; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1