EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Abstract

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 deals with the Prostaglandin E receptor EP4, a member of the EP family of GPCR, as a promising newer therapeutic target for treating breast cancer. We show that aberrant over-expression of cyclooxygenase Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:(COX)-2, an inflammation-associated enzyme, occurring in 40-50% of breast cancer patients leads to tumor progression and metastasis due to multiple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 (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 VEGF-A), lymphangiogenesis (due to upregulation of VEGF-C/D) and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All these events were primarily mediated by activation of the PGE receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all 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 PD-1 or PD-L1 inhibitors.

Arachidonic acid alleviates the detrimental effects of acetylsalicylic acid on human granulosa cells performance in vitro

“…Evidence points a close proportional relation regarding the activity of COX‐2 and aromatase activity, E 2 production,and pregnancy rate (Blom, Tan, Hughes, Tekpetey, & Rafea, 2018; Stevenson & Pulley, 2016). Consistent with our results, serum E 2 concentration among NSAID users was significantly lower than nonusers of NSAIDs (Hudson et al, 2008; Majumder, Nandi, Omar, Ugwuagbo, & Lala, 2018). When the combination of ASA with AA added to CGCs, the synthesis of both E 2 was induced.…”

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

“…Recently, it was shown that COX2/ mPGES1(Ptges)/PGE 2 pathway upregulates PD-L1 expression in tumor-associated macrophages (TAM) and MDSC, which contributes to the immunosuppression in bladder cancer [22]. In addition, upregulated PGE 2 receptor EP4 was found in COX2-expressing triple-negative breast cancer, whereas targeting EP4 was suggested to benefit the therapeutic effect of PD-L1 inhibitors [44].…”

Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation

“…However, anti-cancer drugs that specifically target GPCRs are not currently available [9]. The prostanoid receptors represent the most notable family of validated pharmacological targets in a variety of diseases, including cancer [10].…”