Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.

Abstract

Estrogen synthesis is catalyzed by cytochrome P450 aromatase, which is encoded by the CYP19 gene. In obese postmenopausal women, increased aromatase activity in white adipose tissue is believed to contribute to hormone-dependent breast cancer. Prostaglandin E(2) (PGE(2)) stimulates the cAMP→protein kinase A (PKA) pathway leading to increased CYP19 transcription and elevated aromatase activity in inflamed white adipose tissue. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a major role in the catabolism of PGE(2). Here, we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor PPARγ suppressed aromatase expression. Treatment of human preadipocytes with pioglitazone suppressed Snail, a repressive transcription factor, resulting in elevated levels of 15-PGDH and reduced levels of PGE(2) in the culture medium. Pioglitazone also inhibited cAMP→PKA signaling leading to reduced interaction between phosphorylated cAMP responsive element-binding protein, p300, and CYP19 I.3/II promoter. BRCA1, a repressor of CYP19 transcription, was induced by pioglitazone. Consistent with these in vitro findings, treatment of mice with pioglitazone activated PPARγ, induced 15-PGDH and BRCA1 while suppressing aromatase levels in the mammary gland. Collectively, these results indicate that the activation of PPARγ induces BRCA1 and suppresses the PGE(2)→cAMP→PKA axis leading to reduced levels of aromatase. PPARγ agonists may have a role in reducing the risk of hormone-dependent breast cancer in obese postmenopausal women.