Stromal Adipocyte PPARγ Protects Against Breast Tumorigenesis
Menée sur un modèle murin, cette étude montre que l'activation du récepteur nucléaire PPAR-gamma des adipocytes du stroma mammaire peut réduire la tumorigenèse du sein
Peroxisome proliferator-activated receptor (PPAR)γ regulates the expression of genes essential for fat storage, primarily through its activity in adipocytes. It also has a role in carcinogenesis. PPARγ normally stops the in vivo progression of 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumors as revealed with PPARγ haploinsufficient mice. Since many cell types associated with the mammary gland express PPARγ, each with unique signal patterns, the present study aimed to define which tissues are required for PPARγ-dependent anti-tumor effects. Accordingly, adipocyte-specific PPARγ knockout (PPARγ-A KO) mice and their wild-type (PPARγ-WT) controls were generated, and treated with DMBA for six 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 tumor outcomes. In PPARγ-A KOs versus PPARγ-WT mice, malignant mammary tumor incidence was significantly higher and mammary tumor latency was decreased. DMBA+ROSI treatment reduced average mammary tumor volumes by 50%. Gene expression analyses of mammary glands by qRT-PCR and immunofluorescence indicated that untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes. Compared to PPARγ-WT mice, serum leptin levels in PPARγ-A KOs were also significantly higher throughout the study. Together, these data are the first to suggest that in vivo PPARγ expression in mammary stromal adipocyte attenuates breast tumorigenesis through BRCA1 upregulation and decreased leptin secretion. This study supports a protective effect of activating PPARγ as a novel chemopreventive therapy for breast cancer.
http://carcin.oxfordjournals.org/content/early/2012/05/11/carcin.bgs173.abstract