Abstract 3475: Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis

Abstract

Abstract 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. Using GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms, we 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). Comparison of the metabolite profiles from the tumors identified oncogene-induced metabolic reprogramming of the tumor tissues. To develop a higher order understanding of the driver genes and metabolites in breast cancer, we next developed a discovery-based correlation network analysis that captured interactions between both metabolite and gene expression data. This analysis uniquely identified a metabolic network of metabolites and genes with prognostic value in breast cancer patients, identifying 35 metabolite and 33 gene hubs that are likely integral to breast tumor metabolism. Further MALDI-MS based imaging revealed heterogeneous distribution of hub metabolites between stromal and epithelial tissue in breast tumors from transgenic mouse models, as well as heterogeneity within the tumor epithelium, suggesting complex metabolic landscape even within the tumor epithelium. We initially 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. We 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 cells decreased both proliferation and lung metastatic burden. These data suggest AQP7 promotes invasive phenotypes of breast cancer progression. 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. Citation Format: Chen Dai, Jennifer Arceo, James Arnold, Junmin Wu, Norman J. Dovichi, Arun Sreekumar, Jun Li, Laurie E. Littlepage. Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3475.