Modulation of Host Natural Killer Cell Functions in Breast Cancer via Prostaglandin E2 Receptors EP2 and EP4

Breast malignancies often have high levels of COX-2. The COX-2 product prostaglandin E-2 (PGE(2)) contributes to the high metastatic capacity of breast tumors. Our published data indicate that inhibiting either PGE(2) production or PGE(2)-mediated signaling through the PGE(2) receptor EP4 (1 of 4 EP expressed on the malignant cell) reduces metastasis by a mechanism that requires natural killer (NK) cells. Tumor-derived PGE(2) and exogenous PGE(2) are known to have direct inhibitory effects on NK cell functions, but less is known regarding which EP receptors mediate these effects. We now show that several NK functions (lysis, migration, cytokine production) are compromised in tumor-bearing mice and that tumor-produced PGE(2) interferes with NK cell functions. PGE(2) inhibits the potential of NK cells to migrate, exert cytotoxic effects, and secrete interferon gamma. The ability of PGE(2) to inhibit NK cells from tumor-bearing mice is by acting on EP2 and EP4 receptors. NK cells from tumor-bearing mice were more sensitive to inhibition by EP4 and EP2 agonists compared with endogenous NK cells from healthy mice. PGE(2) was inhibitory to most NK functions of either normal or tumor-bearing mice. In contrast, there was a trend for enhanced tumor necrosis factor alpha production in response to PGE(2) by NK cells from tumor-bearing mice. We also report that a recently described EP4 antagonist, frondoside A, inhibits breast tumor metastasis in an NK-dependent manner and protects interferon gamma production by NK cells from PGE(2)-mediated suppression. Taken together these data show that NK functions are depressed in tumor-bearing hosts relative to normal NK cells and that PGE(2) suppresses NK functions by acting on EP2 and EP4 receptors.