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

• Published in: Molecular cancer 2015-04, Vol.14 (1), p.85-85, Article 85
• Main Authors: Apostoli, Anthony J, Roche, Jennifer M, Schneider, Mark M, SenGupta, Sandip K, Di Lena, Michael A, Rubino, Rachel E, Peterson, Nichole T, Nicol, Christopher J B
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; Animals; BRCA1 Protein - metabolism; Cytokines - blood; Disease Progression; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Deletion; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - blood; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Mammary Neoplasms, Experimental - blood; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mice, Knockout; Models, Biological; Organ Specificity; PPAR gamma - metabolism; Signal Transduction; Tumor Burden
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-015-0347-8

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. 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. 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. 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.