Abstract
BackgroundAmong 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.MethodsPPARγ 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.ResultsCompared 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.ConclusionThese 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 materialThe online version of this article (doi:10.1186/s12943-015-0347-8) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer is the most commonly diagnosed form of cancer among women worldwide with 1.7 million new cases identified and over 500,000 breast cancer-related deaths in 2012 [1]
In regards to tumourigenic response, overall survival (OS) for PPARγ-WT mice (PPARγ)-WT and PPARγ-MG KO mice are shown in Figure 1A and B respectively, and for dimethylbenz [a] anthracene (DMBA) Only-treated and DMBA + ROSI-treated mice are shown in Figure 1C and D respectively
Among DMBA Only-treated groups, PPARγ-MG KO mice showed a strong statistically significant advantage in OS compared to PPARγ-WTs (p < 0.0001); this difference was not retained between DMBA + ROSItreated genotypes
Summary
Breast cancer is the most commonly diagnosed form of cancer among women worldwide with 1.7 million new cases identified and over 500,000 breast cancer-related deaths in 2012 [1]. Peroxisome proliferator-activated receptor (PPAR)γ is a transcription factor that is primarily expressed in adipocytes [2], as well as mammary epithelial (MG) cells [3], and a majority of human breast tumour cell lines [4,5]. It regulates the expression of genes involved in glucose and lipid metabolism, with an emerging role in breast tumourigenesis [6]. The role of PPARγ expression and activation in mammary epithelial cells (MG) with respect to DMBA-mediated breast tumourigenesis was investigated
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