Opposing roles for mammary epithelial-specific PPAR[gamma] 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[gamma] ligands. Keywords: Breast cancer, PPAR[gamma], Mammary epithelial cells, Knockout mouse model, Chemotherapy