THE STROMAL ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA IN BREAST TUMOURIGENESIS
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Breast cancer is the most commonly diagnosed female cancer, and kills 1 in 30 Canadian women, mostly from metastatic disease. Previous studies showed PPARγ decreases breast cancer progression, but due to the many mammary gland-associated cell types expressing PPARγ, each with unique signal patterns, the mechanisms required clarification. To define the mammary stromal role of PPARγ during breast tumourigenesis, cell-type targeted PPARγ knockout (KO) mice were generated, and studied using both chemical carcinogen (DMBA) and multi-risk factor DMBA + protumourigenic high fat diet (ProHF) models. PPARγ adipocyte targeted KO mice (PPARγ-A KO) were more susceptible to DMBA and DMBA+ProHF-induced mammary tumourigenesis than wild-type (PPARγ-WT) controls. In both studies, PPARγ-A KO mice had increased mammary tumour incidences and decreased latency. PPARγ-A KOs also developed more ovarian tumours when treated with DMBA+ProHF. Dietary supplementation with the PPARγ activator rosiglitazone (ROSI) rescued tumourigenic phenotypes in PPARγ-WTs more so than PPARγ-A KOs. Mechanistic studies unveiled untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes, decreased circulating IL-2, IL-13 and MIP-1α, and increased serum leptin. BRCA1 regulates aromatase in adipocytes, IL-2, IL-13 and MIP-1α stimulate immune surveillance, and leptin promotes tumour cell proliferation and angiogenesis. These novel findings suggest that loss of PPARγ in mammary stromal adipocytes exerts both local and systemic protumourigenic signaling changes contributing to breast and ovarian tumourigenesis, and that use of ROSI may be beneficial to some patients. Since human use of ROSI is limited due to peripheral edema, which may stem from vascular endothelial cell (VEC) effects, PPARγ-VEC KO mice were used to unravel the mechanisms. In contrast to PPARγ-WTs, PPARγ-VEC KOs resisted extracellular fluid increases and plasma volume expansion in response to ROSI. FAK and VE-cadherin were also dramatically increased in PPARγ-VEC KO endothelial cell junctions compared to PPARγ-WTs. These studies directly unveil the mechanisms of TZD-induced edema and identify biomarkers to improve the therapeutic window for PPARγ agonists. In the long-term, these studies may help identify susceptible populations, and serve as the basis for novel treatments to prevent deaths among the 24,000 Canadians diagnosed with breast cancer in 2014.