Novel Metabolic Networks Identify Key Metabolic Hubs of Breast Cancer: The Effect of Aquaporin 7 on Breast Cancer Progression

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.</p

Top 10 the most productive organizations.

Top 10 the most productive organizations.</p

Co-occurrence analysis of author keywords.

(A) The network visualization of total author keywords (2,656 items) was conducted. (B) The overlay visualization of co-occurrence analysis of author keywords was presented in VOSviewer, the Weight was an occurrence, and Scores were the average published year. (C) The crosstalk of author keywords was presented.</p

Top 10 countries/regions on chordoma.

Top 10 countries/regions on chordoma.</p

The cooperative relationship between countries was generated by the online bibliometric analysis.

The cooperative relationship between countries was generated by the online bibliometric analysis.</p

Citation analysis of documents.

1,618 documents were cited among 2,118 articles, and 1,438 valid items were connected. (A) The overlay visualization of citation map of documents was generated by Linlog/modularity in VOSviewer, the Weight was citations, and Scores were the average published year. (B) The network visualization was conducted, and the crosstalk of citation documents was presented.</p

Top 10 active authors with most documents.

Top 10 active authors with most documents.</p

Annual number of documents indexed in the WOSCC from 2000 to 2020 by the online bibliometric analysis.

Annual number of documents indexed in the WOSCC from 2000 to 2020 by the online bibliometric analysis.</p

Top 10 Co-citation of cited reference on chordoma.

Top 10 Co-citation of cited reference on chordoma.</p

Co-author analysis of organizations with network visualization.

(A) 1,190 valid items (1,700 total items) were interlinked. (B) The important partners of the top 3 organizations (minimum number of documents of an organization was 10, and 47 organizations met the thresholds). The thickness of lines indicates the strength of the relationship.</p