title: Stromal adipocyte PPARγ protects against breast tumorigenesis.
abstract: Peroxisome proliferator-activated receptor (PPAR)γ regulates the expression of genes essential for fat storage, primarily through its activity in adipocytes. It also has a role in carcinogenesis. PPARγ normally stops the in vivo progression of 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumours as revealed with PPARγ haploinsufficient mice. Since many cell types associated with the mammary gland express PPARγ, each with unique signal patterns, this study aimed to define which tissues are required for PPARγ-dependent antitumour effects. Accordingly, adipocyte-specific PPARγ knockout (PPARγ-A KO) mice and their wild-type (PPARγ-WT) controls were generated, and treated with DMBA for 6 weeks to initiate breast tumorigenesis. On week 7, mice were randomized to continue on normal chow diet or one supplemented with rosiglitazone (ROSI), and followed for 25 weeks for tumour outcomes. In PPARγ-A KO versus PPARγ-WT mice, malignant mammary tumour incidence was significantly higher and mammary tumour latency was decreased. DMBA + ROSI treatment reduced average mammary tumour volumes by 50%. Gene expression analyses of mammary glands by quantitative real-time polymerase chain reaction and immunofluorescence indicated that untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes. Compared with PPARγ-WT mice, serum leptin levels in PPARγ-A KOs were also significantly higher throughout the study. Together, these data are the first to suggest that in vivo PPARγ expression in mammary stromal adipocytes attenuates breast tumorigenesis through BRCA1 upregulation and decreased leptin secretion. This study supports a protective effect of activating PPARγ as a novel chemopreventive therapy for breast cancer.
authors.affiliation: Department of Pathology and Molecular Medicine, Richardson Laboratories, Queen's University, Kingston, Ontario, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Skelhorne-Gross
authors.forename: Alexis L
authors.initials: AL
authors.lastname: Reid
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Apostoli
authors.forename: Michael A
authors.initials: MA
authors.lastname: Di Lena
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rubino
authors.forename: Nichole T
authors.initials: NT
authors.lastname: Peterson
authors.forename: Mark
authors.initials: M
authors.lastname: Schneider
authors.forename: Sandip K
authors.initials: SK
authors.lastname: SenGupta
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Christopher J B
authors.initials: CJ
authors.lastname: Nicol
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D017154:Stromal Cells / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage
chemical_list: D017931:DNA Primers; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone