Aromatase inhibition by 15-deoxy-prostaglandin J(2) (15-dPGJ(2)) and N-(4-hydroxyphenyl)-retinamide (4HPR) is associated with enhanced ceramide production.

Inhibition of aromatase activity is an established endocrine therapy in the treatment of hormone-dependent breast cancer. Recent studies on aromatase inhibition by the synthetic retinoid 4HPR, also known as fenretinide, and the PPARgamma agonist 15-dPGJ(2) have implicated a direct receptor-independent, redox-sensitive mechanism of action. The signalling molecule ceramide has also been previously implicated as a negative regulator of aromatase activity.

Prostaglandin J2 metabolites inhibit aromatase activity by redox-sensitive mechanisms: potential implications for breast cancer therapy.

The mechanisms by which prostaglandin (PG)J(2) metabolites inhibit tumorigenicity are poorly understood but may involve thiol reactivity or peroxisome proliferator-activated receptor (PPAR)-dependent pathways. Because aromatase is an important therapeutic target in breast cancer treatment, we have investigated the effect of PGJ(2) metabolites on aromatase activity and evaluated a potential role for redox status during PGJ(2) metabolite action. 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2)) and 9-deoxy-Delta(9,12)13,14-dihydroPGD(2) (Delta(12)PGJ(2)) caused dose-dependent inhibition of both pre-induced aromatase activity in human breast fibroblasts and MDA MB 231 breast cancer cells and of constitutive aromatase activity in JEG-3 choriocarcinoma cells.