Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression

Background: Among women worldwide, breast cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related deaths. Improved understanding of breast tumourigenesis may facilitate the development of more effective therapies. Peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor that regulates genes involved in insulin sensitivity and adipogenesis. Previously, we showed, using 7,12-dimethylbenz [a] anthracene (DMBA)-treated haploinsufficient PPAR gamma mice, that PPAR gamma suppresses breast tumour progression; however, the PPAR gamma expressing cell types and mechanisms involved remain to be clarified. Here, the role of PPAR gamma expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated. Methods: PPAR gamma MG knockout (PPAR gamma-MG KO) mice and their congenic, wild-type controls (PPAR gamma-WT) were treated once a week for six weeks by oral gavage with 1 mg DMBA dissolved in corn oil and maintained on a normal chow diet. At week 7, mice were randomly divided into those maintained on a normal chow diet (DMBA Only; PPAR gamma-WT: n = 25 and PPAR gamma-MG KO: n = 39) or those receiving a diet supplemented with the PPAR gamma ligand, rosiglitazone (ROSI, 4 mg/kg/day) (DMBA + ROSI; PPAR gamma-WT: n = 34 and PPAR gamma-MG KO: n = 17) for the duration of the 25-week study. Results: Compared to DMBA Only-treated PPAR gamma-WTs, both breast tumour susceptibility and serum levels of proinflammatory and chemotactic cytokines, namely IL-4, eotaxin, GM-CSF, IFN-gamma, and MIP-1 alpha, were decreased among PPAR gamma-MG KOs. Cotreatment with ROSI significantly reduced breast tumour progression among PPAR gamma-WTs, correlating with increased BRCA1 and decreased VEGF and COX-2 protein expression levels in breast tumours; whereas, surprisingly DMBA + ROSI-treated PPAR gamma-MG KOs showed increased breast tumourigenesis, correlating with activation of COX-2. Conclusion: These novel data suggest MG-specific PPAR gamma expression and signaling is critical during breast tumourigenesis, and may serve as a strong candidate predictive biomarker for response of breast cancer patients to the use of therapeutic strategies that include PPAR. ligands.