Metabolic Imaging: A link between Lactate Dehydrogenase A, Lactate and Tumor Phenotype Running title: A link between Lactate Dehydrogenase A and Lactate

Purpose: We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design: LDH-A expression, lactate concentration, glucose utilization and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels (measured by magnetic resonance spectroscopic imaging (MRSI)) and tumor glucose utilization (measured by [F] 2-deoxy-2-fluoro-D-glucose positron emission tomography ([F]FDG-PET)) was assessed in orthotopic breast tumors derived from these cell lines. Results: We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate tenfold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less intense hypoxia staining was observed in the larger 67NR tumors, and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions: Lactate-MRSI has a greater dynamic range than [F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. Research. on May 28, 2017. © 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 15, 2011; DOI: 10.1158/1078-0432.CCR-11-0397