Pioglitazone, a PPARγ agonist, Suppresses CYP19 Transcription: Evidence for Involvement of 15-Hydroxyprostaglandin Dehydrogenase and BRCA1
Menée in vitro et à l'aide d'un modèle murin, cette étude identifie un mécanisme par lequel le pioglitazone, un antidiabétique oral agoniste de PPARγ, pourrait réduire le risque de cancer du sein hormono-dépendant chez les femmes obèses ménopausées
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 E2 (PGE2)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 PGE2. Here we investigated the mechanism by which pioglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor γ (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 PGE2 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 activation of PPARγ induces BRCA1 and suppresses the PGE2→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.