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. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-04 11:45:16.472
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/1406 |
| Date | 04 September 2008 |
| Creators | Roche, JENNIFER |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 45335408 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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