A Comparative Species Approach to Understand the Role of MiRNAs in Mammary Gland Health and Disease
Despite being conserved in structure and function, lactation strategies and disease incidences (e.g., mammary cancer) of mammary glands are highly variable across mammals. Due to these variations, it is possible to take a comparative species approach to identify both conserved and species-specific mechanisms that regulate mammary gland health and disease. Micro(mi)RNAs are promising targets for comparative species studies since they are conserved in structure and are important mediators of mammary growth, lactation, and pathogenesis. Additionally, stable miRNAs released into circulation may serve as indicators of disease state and risk, demonstrating that assessing miRNAs both intra- and inter-cellularly has predictive and diagnostic value. Furthermore, mammary stem and progenitor cells, which facilitate mammary development and are the suspected cells of origin for common mammary cancers, are regulated by miRNAs during homeostatic and diseased states, making them ideal cell models for investigating the roles of shared miRNA functions within mammary glands. The goal of this dissertation was to elucidate how conserved miRNAs across species function as both regulators and indicators of mammary health and disease. Chapter 1 provides extensive background to contextualize the findings described in this dissertation. Chapter 2 describes a comparative species analysis of mammary stem andprogenitor cell populations (a.k.a. mammosphere-derived epithelial cells (MDECs)), and details a novel, human-specific role of miR-92b-3p as a regulator of MDEC self-renewal. Chapter 3 utilizes a method to identify circulating miRNAs indicative of breast cancer risk. This approach compared circulating miRNAs profiles from human patients to miRNA profiles released from MDECs derived from mammals with low or high mammary cancer incidence, demonstrating a novel approach to identify circulating miRNAs released by mammary cells at risk of malignancy. Chapter 4 characterizes a mammary gland xenotransplantation mouse model to study miRNA regulation of mammary glands and cancer pathogenesis across mammals in an in vivo context. Finally, chapter 5 summarizes the key findings and provides discussion on future experiments. Collectively, the work presented has contributed to the understanding of how miRNAs regulate mammary cells and demonstrates the immense value of our comparative species approach to identify both conserved and variable factors that regulate mammary health and disease.