Opposing roles for mammary epithelial-specific PPARγ signaling and activation during breast tumour progression
Autor: | Mark M. Schneider, Nichole Peterson, Sandip SenGupta, Jennifer M Roche, Rachel E. Rubino, Christopher J. Nicol, Anthony J. Apostoli, Michael Di Lena |
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Jazyk: | angličtina |
Předmět: |
medicine.medical_specialty
Cell type Cancer Research PPARγ 9 10-Dimethyl-1 2-benzanthracene DMBA Peroxisome proliferator-activated receptor Mammary Neoplasms Animal Biology Models Biological Breast cancer Mammary Glands Animal Internal medicine medicine Chemotherapy Animals skin and connective tissue diseases Transcription factor Mice Knockout chemistry.chemical_classification BRCA1 Protein Research Mammary Neoplasms Experimental Cancer Epithelial Cells medicine.disease Tumor Burden 3. Good health PPAR gamma Knockout mouse model Endocrinology chemistry Oncology Organ Specificity Adipogenesis Disease Progression Cancer research Cytokines Molecular Medicine Female Signal transduction Gene Deletion Mammary epithelial cells Signal Transduction |
Zdroj: | Molecular Cancer |
ISSN: | 1476-4598 |
DOI: | 10.1186/s12943-015-0347-8 |
Popis: | 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. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0347-8) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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