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Description

Despite advances in the treatment of newly diagnosed breast cancer (BC), recurrent disease is expected to kill 40,000 women in the US this year. This sobering mortality figure is due to the lack of preventive measures and cures for advanced tumors. In addition, many women with early stage BC, such as ductal carcinoma in situ (DCIS), will unnecessarily receive toxic treatments because of a lack of tools to discriminate between dormant BCs and those that will progress or recur. The roles of two coordinately activated oncogenes, RON which encode a receptor tyrosine kinase and DEK which encodes a chromatin-associated protein, in distinguishing dormant from aggressive BC, and in driving metastasis and tumor recurrence following treatment. RON is frequently overexpressed in human BC, and RON over-expression is sufficient to induce metastatic BC in mice. DEK is also highly expressed, and is important for BC growth and invasion. RON-DEK signaling increases intracellular glutamine production to sustain key metabolites used for macromolecule and energy production. Additional reprogramming of metabolism may occur that can only be adequately identified by tracer technologies. Preliminary data uncovered a novel relationship between the RON-DEK axis and metabolic reprogramming. DEK overexpression increased the accumulation of glycolytic end products (e.g. lactate, NAD+ and alanine) - revealed by 1-D NMR metabolomics and Seahorse analysis. Further, RON and DEK independently promoted the transcriptional expression of enzymes that regulate glycolysis, lactic acid fermentation and cholesterol synthesis. Therefore, we posit that joint inhibition of glycolysis and cholesterol synthesis in patients with BC may be a feasible approach for the prevention of BC progression. Taken together, our data suggest that RON- DEK signaling acts through ?-catenin to reprogram metabolic flux for sustaining energy and macromolecule synthesis required for BC progression. This reprogramming will be defined in atom-resolved detail in Aim 2. The goals of the study are to determine the metabolic consequences of the cooperation between DEK and RON overexpression in breast cancer cells and tumor xenografts using stable isotope resolved metabolomics (SIRM), and thereby identify the metabolic networks that are impacted by these proteins.
StatusFinished
Effective start/end date4/1/203/31/24

Funding

  • University of Cincinnati: $181,188.00

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