The Mammary Epithelial Contribution Of PPARγ In Breast Tumourigenesis
Apostoli, Anthony J.
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Previous studies with peroxisome proliferator-activated receptor (PPAR)γ heterozygous mice suggest PPARγ normally suppresses 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumour progression, but the mechanisms and cell types involved remain unknown. This thesis elucidates the mammary epithelial role of PPARγ during DMBA- and multi-risk factor (DMBA+protumourigenic high fat diet (ProHF))-mediated breast tumourigenesis. Studies were performed using nulliparous mammary epithelial (MG) cell- and postlactational mammary secretory epithelial (MSE) cell-targeted PPARγ knockout (KO) mice. Surprisingly, the first study revealed that PPARγ-MG KOs had decreased DMBA-induced mammary tumourigenesis compared to congenic wildtype (PPARγ-WT) controls. In contrast, cotreatment with a PPARγ activator was protective in PPARγ-WTs, but worsened breast tumour progression in PPARγ-MG KOs. In the second study, MSE-targeted PPARγ deletion generated a significantly increased protumourigenic mammary gland microenvironment and enhanced DMBA-mediated breast tumourigenesis, suggestive of critical epithelial-stromal cell crosstalk. Cotreatment with a PPARγ activator was protective in PPARγ-WT but not PPARγ-MSE KOs during DMBA- induced mammary tumourigenesis, suggesting critical antibreast cancer signaling within MSEs is PPARγ-dependent. In the third study, DMBA+ProHF treatment significantly increased primary breast tumourigenesis in PPARγ-WTs and lung metastases among PPARγ-MSE KOs. Cotreatment with a PPARγ activator was protective only among PPARγ-WTs. Collectively, these data unveil PPARγ expression and signaling in MG and MSE cells as a candidate prognostic and predictive biomarker for breast cancer, and add further support for the novel chemotherapeutic role of PPARγ activation for a subpopulation of breast cancer patients.