Prostaglandin E2 EP receptors as therapeutic targets in breast cancer

Abstract

Prostaglandins are lipid compounds that mediate many physiological effects. Prostaglandin E2 (PGE(2)) is the most abundant prostanoid in the human body, and synthesis of PGE(2) is driven by cyclooxygenase enzymes including COX-2. Both elevated expression of COX-2 and increased PGE(2) levels have been associated with many cancers including breast cancer. PGE(2) exerts its effect by binding to the E series of prostaglandin receptors (EP) which are G protein-coupled receptors. Four EP receptor subtypes exist, EP1-4, and each is coupled to different intracellular signaling pathways. As downstream effectors of the COX-2 pathway, EP receptors have been shown to play a role in breast and other malignancies and in cancer metastasis. The role of each EP receptor in malignant behavior is complex and involves the interplay of EP receptor signaling on the tumor cell, on stromal cells, and on host immune effector cells. While preclinical and epidemiological data support the use of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors (COXibs) for the prevention and treatment of malignancy, toxicities due to COXibs as well as less than promising results from clinical trials have laboratories seeking alternative targets. As knowledge concerning the role of EP receptors in cancer grows, so does the potential for exploiting EP receptors as therapeutic targets for the treatment or prevention of cancer and cancer metastasis.

Fig 1

Eicosanoid biosynthesis and EP receptor signaling pathway. A) Phospholipids from the plasma membrane are mobilized and coverted to arachidonic acid (AA) by phospholipase A2 (PLA₂). COX enzymes convert AA to prostaglandin H2 (PGH₂) precursor molecule which is then converted to prostaglandin E2 (PGE₂) by the synthase molecule PGES. Once produced PGE₂ can exert its effects in one of two ways. 1) PGE₂ can be exported into the extracellular microenvironment by multidrug resistance-associated protein four (MRP4) where PGE₂ can bind to its cognate receptors, the E-series of prostaglandin receptors (EP) on the plasma membrane of a tumor cell, stromal cell or immune effector cell such as a T or Natural Killer (NK) cell. 2) After being synthesized by PGES, PGE₂ can directly act on EP receptors located on the nuclear membrane. After binding its receptor, PGE₂ can be transported back into the cytoplasm through a passive mechanism or actively through a prostaglandin transporter (PGT). PGE₂ is inactivated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and converted to 15-keto-PGE₂. B) EP receptors are G-protein coupled receptors of which four subtypes exist: EP1, EP2, EP3 and EP4. Each receptor is coupled to a different intracellular signaling pathway. The EP2 and EP4 receptors are linked to stimulation of cyclic AMP (cAMP) and protein kinase A (PKA) signaling through sequential activation of Gαs and adenylate cyclase (AC). EP4 can also activate phosphoinositide-3-kinase (PI3K) through Gαi. The EP1 receptor leads to elevation of intracellular calcium through Gαq. EP3 exists in multiple isoforms which are generated through alternative splicing and differing at their carboxy terminal tail. These isoforms are capable of eliciting different intracellular responses through multiple signal transduction pathways. The majority of the isoforms act to inhibit cAMP generation via Gαi. Ligand binding can also lead to an increase in IP3/ intracellular calcium. Another isoform can act to stimulate adenylyl cyclase leading to an increase in cAMP. On immune effector cells, PGE₂ acting through the EP receptors can modulate the function of various immune effector cells. PGE₂ acting through its cognate receptor can inhibit NK cell activity and cytotoxic T cell proliferation leading to a decrease in target cell lysis. C) There is now growing evidence to support perinuclear and/or nuclear localization of functional EP receptors. To date EP1, EP2, EP3α, and EP4 have been shown to be colocalized at the nuclear membranes of a variety of cell types and tissues. Nuclear EP receptors could exert different effects from their plasma membrane counterparts; however, the signaling pathways for nuclear receptors have yet to be determined.