Delineating Novel Genetic and MicroRNA Regulatory Mechanisms in Aggressive Subtypes of Breast Cancer

Abstract

Breast cancer will be diagnosed in over 26,500 Canadians this year. Despite advances, identifying who will develop aggressive breast tumours or who will respond to treatment remains a clinical challenge. This dissertation aimed to delineate novel genetic and microRNA (miRNA) regulatory mechanisms that may contribute to metastases and poor clinical outcomes among patients with aggressive subtypes of breast cancer; those overexpressing human epidermal growth factor receptor 2 (HER2+) and triple negative breast cancer (TNBC). The first component of my thesis focuses on the study of miRNAs, small non-coding RNA molecules that negatively regulate gene expression at the post-transcriptional level to function as both oncogenes and tumour suppressors in breast cancer. We used next generation sequencing to define miRNA expression profiles that correlate with clinical outcomes among a local TNBC patient cohort. My data unveiled new prognostic and predictive miRNA biomarkers significantly correlated with improved overall, relapse-free survival and treatment response among TNBC patients. The second component of my thesis focuses on the study of peroxisome proliferatoractivated receptor (PPAR)g, a transcription factor that controls the expression of genes essential for normal metabolism of fats and sugars in the body. This study used unique in vitro and in vivo models to assess the effects of targeted PPARg deletion in the same HER2+ transformed mammary epithelial cells that drive breast tumour progression. My data are the first to suggest PPARg loss enhances the initiation but not the progression of HER2+ breast cancer, while PPARg ligand treatment decreases these effects. Together, my research elucidates new signaling pathways and therapeutic strategies that may reduce deaths and improve clinical outcomes for HER2+ and TNBC patients.