Understanding the Metabolic and Genetic Regulation of Breast Cancer Recurrence Using Magnetic Resonance-Based Integrative Metabolomics

Breast cancer is the most commonly diagnosed malignancy in women and is the leading cause of cancer-related death in the female population worldwide. In these women, breast cancer recurrence--local, regional, or distant--represents the principal cause of death from this disease. The mechanisms underlying tumor recurrence remain largely unknown. To dissect those mechanisms, our laboratory has developed inducible transgenic mouse models that accurately recapitulate key features of the natural history of human breast cancer progression: primary tumor development, tumor dormancy and recurrence. Dysregulated metabolism has long been known to be a key feature in tumorigenesis. Yet, very little is known about the connection, if any, between cellular metabolic changes and breast cancer recurrence. In this work, I design and implement a systems engineering-based approach, magnetic resonance-based integrative metabolomics, to better understand the metabolic and genetic regulation of breast cancer recurrence. Through a combination of 1H and 13C magnetic resonance spectroscopy (MRS), mass spectrometry (MS) as well as gene expression profiling and functional metabolic and genetic studies, I aim to identify the metabolic profile of mammary tumors during breast cancer progression, identify the molecular basis and role of differential glutamine uptake and metabolism in breast cancer recurrence and finally, investigate the molecular basis and role of differential lactate production in breast cancer recurrence. The findings suggest an evolving metabolic phenotype of tumors during breast cancer progression as well as metabolic dysregulation in some of the key regulatory nodes that control that evolution. Identifying the metabolic changes associated with tumor recurrence can pave the way for identifying novel diagnostic strategies and therapeutic targets that can contribute to improved clinical management and outcome for breast cancer patients.