title: Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. anthony.apostoli@uhnresearch.ca.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Apostoli
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. rochej@aecl.ca.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Roche
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. 3mms4@queensu.ca.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Schneider
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. sengupts@kgh.kari.net.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: SenGupta
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. mdile045@uottawa.ca.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Di Lena
authors.affiliation: Division of Cancer Biology and Genetics, Queen's Cancer Research Institute (QCRI), Kingston, ON, Canada. rubinor@queensu.ca.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rubino
authors.affiliation: Division of Cancer Biology and Genetics, Queen's Cancer Research Institute (QCRI), Kingston, ON, Canada. nicki.peterson@queensu.ca.
authors.forename: Nichole T
authors.initials: NT
authors.lastname: Peterson
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada. nicolc@queensu.ca.|Division of Cancer Biology and Genetics, Queen's Cancer Research Institute (QCRI), Kingston, ON, Canada. nicolc@queensu.ca.|Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. nicolc@queensu.ca.
authors.forename: Christopher J B
authors.initials: CJ
authors.lastname: Nicol
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity; D047495:PPAR gamma / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D019313:BRCA1 Protein; D016207:Cytokines; D047495:PPAR gamma; D015127:9,10-Dimethyl-1,2-benzanthracene