Stromal adipocyte PPAR protects against breast tumorigenesis

Peroxisome proliferator-activated receptor (PPAR) regulates the expression of genes essential for fat storage, primarily through its activity in adipocytes. It also has a role in carcinogenesis. PPAR normally stops the in vivo progression of 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumours as revealed with PPAR haploinsufficient mice. Since many cell types associated with the mammary gland express PPAR, each with unique signal patterns, this study aimed to define which tissues are required for PPAR-dependent antitumour effects. Accordingly, adipocyte-specific PPAR knockout (PPAR-A KO) mice and their wild-type (PPAR-WT) controls were generated, and treated with DMBA for 6 weeks to initiate breast tumorigenesis. On week 7, mice were randomized to continue on normal chow diet or one supplemented with rosiglitazone (ROSI), and followed for 25 weeks for tumour outcomes. In PPAR-A KO versus PPAR-WT mice, malignant mammary tumour incidence was significantly higher and mammary tumour latency was decreased. DMBA + ROSI treatment reduced average mammary tumour volumes by 50%. Gene expression analyses of mammary glands by quantitative real-time polymerase chain reaction and immunofluorescence indicated that untreated PPAR-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes. Compared with PPAR-WT mice, serum leptin levels in PPAR-A KOs were also significantly higher throughout the study. Together, these data are the first to suggest that in vivo PPAR expression in mammary stromal adipocytes attenuates breast tumorigenesis through BRCA1 upregulation and decreased leptin secretion. This study supports a protective effect of activating PPAR as a novel chemopreventive therapy for breast cancer.