Metabolic and Proteomic Adaptations of Metastatic Processes in Breast Cancer Cells

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Developments of targeted therapies improved prognoses and outcomes of patients with localized breast tumors. However, treatment options become limited upon occurrence of metastasis, a spread of tumors to distant organs, as surgical removal of tumors are difficult and tumor cells resist to therapies. Tumor cells need to overcome hurdles such as limited access to oxygen, through hypoxia, and matrix detachment during metastasis. To better understand underlying mechanism enabling tumor cells to overcome the two stresses, metabolic and proteomic changes of breast tumor cells when faced with inhibited oxidative phosphorylation (OXPHOS), a model of hypoxia, and detachment are analyzed. To explore the influence of nutrients on protein expression and that of protein expression on metabolism, Chapter 2 of this dissertation presents a review of previous findings in studies on vitamin intakes affecting tissue proteomes. Metabolic fluxes reflecting cellular utilization of metabolic pathways are quantified with stable isotope tracing, which needs correction for abundances of naturally occurring isotopes if mass isotopologue distributions are directly used to infer fluxes. Chapter 3 introduces a computational tool, PolyMID, which corrects for abundances of naturally occurring isotopes. Among metabolic fluxes, that through pyruvate carboxylase (PC) is reported iii to be altered upon breast cancer-derived lung metastasis. However, work presented in Chapter 4 shows that the widely used method to quantify PC flux is inaccurate, and covers the development of a metabolic flux analysis-based approach with improved performance. Utilizing the above-mentioned tools, the work presented in Chapter 4 continues with analyses of metabolic and proteomic changes in breast cancer cells upon OXPHOS inhibition and culture in suspension. Protein networks regulating metabolic fluxes are identified. PC flux and its positively correlated protein network upon OXPHOS inhibition are found to be negatively correlated in cells resistant to detachment upon culture in forced suspension. Exposure to hypoxia elevates anchorage-independence of the detachment-resistant breast cancer cells. Taken together, hypoxia and matrix detachment induce metabolic and proteomic changes affecting metastatic potential of breast cancer cells.

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161 pages


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Vacanti, Nathaniel

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Sethupathy, Praveen
Schroeder, Frank
O'Brien, Kimberly

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Ph. D., Nutrition

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Doctor of Philosophy

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dissertation or thesis

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