Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1.
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.
Department of Medicine, Weill Cornell Cancer Center, New York, NY 10065, USA. ksubba@med.cornell.edu
Kotha
K
Subbaramaiah
Louise R
LR
Howe
Xi Kathy
XK
Zhou
Peiying
P
Yang
Clifford A
CA
Hudis
Levy
L
Kopelovich
Andrew J
AJ
Dannenberg
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D045162:Thiazolidinediones; D014157:Transcription Factors; D000242:Cyclic AMP; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001141:Aromatase; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D000077205:Pioglitazone