Date of Award
Metastatic breast cancers show distinct preferences to metastasize to lung and bone tissue. Transcriptomic analysis of lung-specific (LM) and bone-specific (BoM) subclones derived from the MDA-231 breast cancer line have identified differential expression of genes that may mediate this tissue-specific metastasis, but metabolic differences have not been systematically studied. If common metabolic phenotypes emerge in metastatic cancers having preferences for different organs, then such ‘metabolic plasticity’ may offer new therapeutic targets for treatment of specific metastases. Changes in glutathione (GSH) and serine synthesis may contribute to tissue-specific proliferation because of their roles in redox homeostasis, biosynthetic reactions including nucleotide synthesis, and/or energy metabolism. This study tests the hypothesis that glucose flux to serine, serine flux through the folate cycle, and glutamine flux to GSH differ between the parent MDA-231 breast cancer line, the LM and BoM lines, and the less malignant T47D breast cancer line. Using a combination of approaches including analysis of 13C serine enrichment from [1,2-13C] glucose by mass spectrometry and metabolic flux analysis, LM and BoM lines exhibited greater rates of serine synthesis than the T47D line, while there was no flux of glucose to serine in MDA-231 cells. Notably, LM and BoM serine synthesis was sufficiently high to negatively affect glycolysis, presumably through the NADH:NAD ratio. Folate cycle fluxes in LM and BoM lines were generally greater than those in T47D cells, as determined by metabolic flux analysis; these fluxes could not be determined in MDA-231 cells since glucose was not used to synthesize serine. LM cells exhibited no detectable GSH synthesis, while approximately 10% of the glutamine consumed by the other three lines was used for GSH synthesis, as determined by BSO-sensitive glutamine consumption. Higher glucose flux to serine in the BoM and LM lines are likely related to their higher proliferation rates rather than their specificity for metastasis to bone or lung. The lack of BSO-sensitive glutamine consumption in LM cells was surprising, and implies that this cell line may rely more on peroxiredoxin and/or thioredoxin than GSH for redox homeostasis. Further studies with different lung and bone-specific cancer lines are necessary to determine if unique metabolic phenotypes exist for these metastatic cancers.
Thornton, Noah, "Serine and Glutathione Biosynthesis in Breast Cancer Subclones That Preferentially Metastasize to Lung and Bone" (2021). Honors Theses. 1852.
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