THE ADIPOCYTE AND ENDOTHELIAL CELL-SPECIFIC ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA IN BREAST TUMOURIGENESIS
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Peroxisome proliferator-activated receptor (PPAR)γ plays a role in tumorigenesis. Previous studies with PPARγ(+/-) mice suggest PPARγ normally suppresses dimethylbenz[a]anthracene (DMBA)-induced breast, and other, tumor progression. Since many cell types associated with the mammary gland express PPARγ, each with unique signaling pathways, the present study aimed to define which tissues are required for PPARγ-dependent anti-tumor effects. Conditional adipocyte and endothelial cell-specific PPARγ knockout mice (PPARγ-A KO and PPARγ-E KO respectively) were used to evaluate whether PPARγ signaling normally acts to prevent DMBA-mediated breast tumour progression in a stromal cell-specific manner. Twelve week old PPARγ KO mice and their congenic wildtype (WT) controls were randomly assigned to one of two treatment groups. All mice were treated by gavage once/week for 6 weeks with 1 mg DMBA and maintained on a normal chow diet. At week 7, mice in each group were divided into those continuing normal chow, and those receiving a PPARγ ligand (ROSI, 4 mg/kg/day) supplemented diet for the duration of the 25 week study, and monitored weekly. Tumour and tissue samples were collected at necropsy, and portions of each were fixed and frozen for future analysis. In both PPARγ-A KOs and PPARγ-E 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. In the PPARγ-E KO mice, both treatment groups saw a significant increase in thymic tumour incidence, a finding not established before with the study of other stromal cell knockout mice. These studies provide the first direct in vivo evidence that PPARγ signalling in stromal adipocytes and endothelial cells attenuates DMBA-mediated breast tumourigenesis. This study supports a protective effect of activating PPAR gamma as a novel chemopreventive therapy for breast cancer.