| First Author | Apostoli AJ | Year | 2015 |
| Journal | Mol Cancer | Volume | 14 |
| Pages | 85 | PubMed ID | 25889730 |
| Mgi Jnum | J:316502 | Mgi Id | MGI:6837526 |
| Doi | 10.1186/s12943-015-0347-8 | Citation | Apostoli AJ, et al. (2015) Opposing roles for mammary epithelial-specific PPARgamma signaling and activation during breast tumour progression. Mol Cancer 14:85 |
| abstractText | 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 PPARgamma mice, that PPARgamma suppresses breast tumour progression; however, the PPARgamma expressing cell types and mechanisms involved remain to be clarified. Here, the role of PPARgamma expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated. METHODS: PPARgamma MG knockout (PPARgamma-MG KO) mice and their congenic, wild-type controls (PPARgamma-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; PPARgamma-WT: n = 25 and PPARgamma-MG KO: n = 39) or those receiving a diet supplemented with the PPARgamma ligand, rosiglitazone (ROSI, 4 mg/kg/day) (DMBA + ROSI; PPARgamma-WT: n = 34 and PPARgamma-MG KO: n = 17) for the duration of the 25-week study. RESULTS: Compared to DMBA Only-treated PPARgamma-WTs, both breast tumour susceptibility and serum levels of proinflammatory and chemotactic cytokines, namely IL-4, eotaxin, GM-CSF, IFN-gamma, and MIP-1alpha, were decreased among PPARgamma-MG KOs. Cotreatment with ROSI significantly reduced breast tumour progression among PPARgamma-WTs, correlating with increased BRCA1 and decreased VEGF and COX-2 protein expression levels in breast tumours; whereas, surprisingly DMBA + ROSI-treated PPARgamma-MG KOs showed increased breast tumourigenesis, correlating with activation of COX-2. CONCLUSION: These novel data suggest MG-specific PPARgamma 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 PPARgamma ligands. |
