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

Hiken, Jeffrey F.; McDonald, James I.; Decker, Keith F.; Sánchez, César; Hoog, Jeremy; VanderKraats, Nathan D.; Jung, Kyle L.; Akinhanmi, Margaret; Rois, Lisa E.; Ellis, Matthew J.; Edwards, John

doi:10.1038/onc.2016.397

Cited by 21 publications

(13 citation statements)

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“…More recently, EP4 has been implicated in treatment resistance and as a driver of CSCs. Epigenetic activation of the EP4 receptor may support resistance to endocrine therapy in patients with breast cancer that is reversed by GW627368x (Hiken et al, 2017). Several labs have shown that EP4 is upregulated in malignant cells with stem-like properties and that treatment of tumorbearing mice with EP4 antagonists (RQ15986, AH23848, Frondoside A) reduces the number of CSC (Kundu et al, 2014;Majumder et al, 2014).…”

Section: Cancer Stem Cells and Ep4 In Chemoresistancementioning

confidence: 99%

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

2020

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The cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E 2 (PGE 2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-kB. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE 2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE 2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immunebased therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies.

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Section: Cancer Stem Cells and Ep4 In Chemoresistancementioning

confidence: 99%

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

2020

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“…Upregulation of the sphingosine 1-phosphate (S1P) 3 receptor in highly metastatic variants of a breast cancer cell line was shown to increase migration and invasion by the induction of PGE2 and EP2/EP4 activation [ 65 ]. Genome-wide DNA methylation and expression analysis of breast cancer cell line models of acquired estrogen resistance indicated that the EP4 receptor was upregulated by epigenetic mechanisms in demethylation resistant breast cancer cells [ 66 ]. In this study, EP4 was shown to be essential for estrogen-independent growth resulting from the activation of the ERα-cofactor CARM1.…”

Section: Cox2/pge2 Mediated Cancer Progressionmentioning

confidence: 99%

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Majumder

Nandi

Omar

et al. 2018

IJMS

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G-protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G-protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5′-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions, as well as in the pathology of many diseases, including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review briefly summarizes the signaling pathways utilized by the EP (prostaglandin E receptor) family of GPCR, their physiological and pathological roles in carcinogenesis, with special emphasis on the roles of EP4 in breast cancer progression. We make a case for EP4 as a promising newer therapeutic target for treating breast cancer. We show that an aberrant over-expression of cyclooxygenase (COX)-2, which is an inflammation-associated enzyme, occurring in 40–50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune cells, such as Natural Killer (NK) and T cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis, due to upregulation of multiple angiogenic factors including Vascular Endothelial Growth Factor (VEGF)-A, increased lymphangiogenesis (due to upregulation of VEGF-C/D), and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All of these events were primarily mediated by activation of the Prostaglandin (PG) E receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all of these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs—miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients for monitoring SLC-ablative therapies, such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers, such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents, such as inhibitors of programmed cell death (PD)-1 or PD-L1.

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“…Gains are cancer-specific and normally include non-DNA-methylated CpG islands located in large regions of proximal promoters. These changes can be related to loss of gene expression, very similar to inactivating mutations on the abolition of tumor suppressor gene function through linked gene silencing; however, the activation of oncogenes also may occur 77 . In addition to DNA methylation, chromatin abnormalities are also observed in various types of tumors 78 .…”

Section: Genetic Heterogeneitymentioning

confidence: 99%

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

Esparza-López

Escobar-Arriaga

Soto-Germes

et al. 2017

RIC

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In recent years, it has become evident that intra-tumor heterogeneity of breast cancer is a big challenge for the diagnosis, treatment, and clinical course of tumor-bearing patients. The advances in molecular biology and other technologies have led to the knowledge that a breast cancer tumor is comprised of multiple cellular entities. Here we review the two theories that have been described, trying to explain the origin of intra-tumor heterogeneity: clonal evolution and cancer stem cells. The first one considers that a single cell gives rise to many subpopulations through the accumulation of multiple aberrations, while the cancer stem cells theory foresees a hierarchical tumor evolution where only a few cells with self-renewal capacity give rise to different subpopulations. We also analyze the genetic, epigenetic, and microenvironment contributions to breast cancer intra-tumor heterogeneity. Finally, the clinical and therapeutic impact of intra-tumor heterogeneity on the outcome of breast cancer patients is discussed. (REV INVES CLIN. 2017;69:66-76)

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

Cited by 21 publications

References 50 publications

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

Eicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapy

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Breast Cancer Intra-Tumor Heterogeneity: One Tumor, Different Entities

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