THE MAMMARY EPITHELIAL CELL-SPECIFIC ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ IN DMBA-MEDIATED BREAST TUMOURIGENESIS
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Breast cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related deaths, among women world-wide. 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 the genes involved in insulin sensitivity and adipogenesis. In vitro and in vivo studies also suggest that PPARγ suppresses breast tumour progression; however, the mechanisms remain to be clarified. In the current study, I investigated the mammary epithelial cell-specific role of PPARγ in 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumourigenesis. Mammary epithelial cell-specific PPARγ knockout (PPARγ-MG KO) mice and their congenic, wild-type controls (PPARγ-WT) were treated with either DMBA alone or in combination with a PPARγ ligand (rosiglitazone)-supplemented diet, and followed for tumour formation. DMBA-mediated mammary tumour multiplicity decreased 4.5-fold among PPARγ-WT, but only 1.2-fold in PPARγ-MG KO mice upon co-treatment with rosiglitazone. Similarly, compared to respective DMBA alone groups, mammary tumour volumes were decreased, and onset was delayed, more among DMBA + Rosiglitazone treated PPARγ-WT versus PPARγ-MG KO mice. To assess whether DMBA could alter cell growth, in vitro studies using two human breast cancer cell lines were performed. Human MCF-7 and MDA-MB-231 cells were treated with DMBA, rosiglitazone or both, and assessed for changes in proliferation, apoptosis and target gene expression. DMBA exerted minimal effects on proliferation; whereas, treatments induced apoptosis in MCF-7, and necrosis in MDA-MB-231, cells. The expression of MCF-7 PPARγ1 protein increased with all treatments, while MDA-MB-231 PPARγ2 protein and BRCA1 mRNA expression increased following rosiglitazone or co-treatment. This work advances our understanding of the mammary epithelial cell-specific role of PPARγ signaling in DMBA-mediated breast tumourigenesis, and supports a role for PPARγ activation in the suppression of breast tumour progression. These findings may assist with the development of more effective anti-breast cancer agents.