The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. In this thesis, I quantified and compared the levels of 374 metabolites in breast tumor tissue from normal tissue and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-Db, Wnt1, Neu, and C3-TAg). I identified oncogene-specific metabolic profiles and used these model-specific metabolites to predict patient survival. Except for C3-TAg-specific metabolites, the model-specific metabolites were unable to predict survival in breast cancer patients.
To further identify the critical metabolic players in breast cancer, we developed a correlation-based network analysis that captures the interactions between metabolic profiling and gene expression data. Our network analysis identified 35 metabolite and 33 gene hubs that had the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer.
I then focused on the gene hub aquaporin-7 (Aqp7), a water and glycerol channel protein, as a novel regulator of breast cancer. AQP7 deficiency in animal models is associated with adipocyte hypertrophy, increased glycerol and triglyceride accumulation, insulin resistance, and obesity. I discovered that AQP7 is a prognostic marker of overall survival and metastasis in breast cancer patients. Aqp7 is expressed in the epithelium and adipocytes in normal and tumor breast tissue. Reduced Aqp7 expression in mouse breast cancer models leads to reduced primary tumor burden and lung metastasis. These data suggest Aqp7 as a target of breast cancer treatment. Further metabolomics and complex lipid profiling of the cells and tumors revealed dramatically altered amino acid, carbohydrate, nucleotide, and lipid metabolism, including lowered glutathione levels and increased lipid levels in Aqp7 knockdown cells and tumors compared to scrambled control. Using cell-based assays, we confirmed that Aqp7 knockdown decreased the oxidative stress tolerance of cancer cells, and altered the usage of arginine.
Using an unbiased, discovery-based approach, this study shed light on important players in breast cancer metabolism from a new perspective that complements current guided network analyses.