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

Oncogene volume 36, pages 2319–2327 (2017)Cite this article

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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 E2 receptor 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.

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Acknowledgements

We thank C de Guzman-Strong and S Matkovich for their comments on the manuscript. This work was supported by grants NIH R00 CA127360, NIH R21 LM011199, NIH 2T32GM007067-37, Department of Defense W81XWH-11-1-0401 and a Siteman Cancer Center Breast Cancer Program career development award to JRE. We also thank the Genome Technology Access Center at the Washington University School of Medicine for help with genomic analysis (partially supported by NIH P30 CA91842 and NIH UL1 TR000448).

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Authors and Affiliations

  1. Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA

    J F Hiken, J I McDonald, K F Decker, N D VanderKraats, K L Jung, M Akinhanmi, L E Rois & J R Edwards

  2. Haematology–Oncology Department, Cancer Programme, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile

    C Sanchez

  3. Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    J Hoog

  4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    M J Ellis

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  1. J F Hiken
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Correspondence to J R Edwards.

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Dr Ellis has received consulting fees from Pfizer, Novartis and AstraZenica. He has ownership and patent income from Bioclassifier LLC for the PAM50 breast cancer test Prosigna sold by Nanostring. The remaining authors declare no conflict of interest.

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Hiken, J., McDonald, J., Decker, K. et al. Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer. Oncogene 36, 2319–2327 (2017). https://doi.org/10.1038/onc.2016.397

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