1. Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression.
- Author
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Apostoli AJ, Roche JM, Schneider MM, SenGupta SK, Di Lena MA, Rubino RE, Peterson NT, and Nicol CJ
- Subjects
- 9,10-Dimethyl-1,2-benzanthracene, Animals, BRCA1 Protein metabolism, Cytokines blood, Epithelial Cells pathology, Female, Gene Deletion, Mammary Glands, Animal pathology, Mammary Neoplasms, Animal blood, Mammary Neoplasms, Animal pathology, Mammary Neoplasms, Experimental blood, Mammary Neoplasms, Experimental pathology, Mice, Knockout, Models, Biological, Organ Specificity, Tumor Burden, Disease Progression, Epithelial Cells metabolism, Mammary Glands, Animal metabolism, Mammary Neoplasms, Animal metabolism, Mammary Neoplasms, Experimental metabolism, PPAR gamma metabolism, Signal Transduction
- Abstract
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)γ 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 PPARγ mice, that PPARγ suppresses breast tumour progression; however, the PPARγ expressing cell types and mechanisms involved remain to be clarified. Here, the role of PPARγ expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated., Methods: PPARγ MG knockout (PPARγ-MG KO) mice and their congenic, wild-type controls (PPARγ-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; PPARγ-WT: n = 25 and PPARγ-MG KO: n = 39) or those receiving a diet supplemented with the PPARγ ligand, rosiglitazone (ROSI, 4 mg/kg/day) (DMBA + ROSI; PPARγ-WT: n = 34 and PPARγ-MG KO: n = 17) for the duration of the 25-week study., Results: Compared to DMBA Only-treated PPARγ-WTs, both breast tumour susceptibility and serum levels of proinflammatory and chemotactic cytokines, namely IL-4, eotaxin, GM-CSF, IFN-γ, and MIP-1α, were decreased among PPARγ-MG KOs. Cotreatment with ROSI significantly reduced breast tumour progression among PPARγ-WTs, correlating with increased BRCA1 and decreased VEGF and COX-2 protein expression levels in breast tumours; whereas, surprisingly DMBA + ROSI-treated PPARγ-MG KOs showed increased breast tumourigenesis, correlating with activation of COX-2., Conclusion: These novel data suggest MG-specific PPARγ 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 PPARγ ligands.
- Published
- 2015
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