CHANGES IN THE METABOLIC PROFILE OF MDA‐MB231 BREAST CANCER DUE TO LDHA AND LDHB DOUBLE KNOCKOUT

Abstract

PURPOSETriple Negative Breast Cancer (TNBC) is an aggressive form of cancer that disproportionately affects African Americans and has a high mortality rate with no known cure. All solid tumors display an elevated glycolytic flux accounting for increased levels of lactic acid production, which is believed to be driven by the various isoforms of the enzyme Lactate Dehydrogenase (LDH). LDHA and LDHB are highly expressed in MDA‐MB‐231 cells. Increased lactic acid secretion contributes to significant pro oncogenic malignant and metastatic processes.METHODSEdited MDA‐MB 231 TNBC cells with LDHA and LDHB double gene knockouts were provided by Snynthego from their engineered cell product, knockout cell pool. The effects of LDHA and LDHB double knockouts on genetic parameters in MDA‐MB‐231 cells were evaluated by examining whole transcriptomic influence on mRNAs and long intergenic non‐coding RNA transcripts (lincRNA) using Affymetrix human 2.1‐ST microarrays. Genome studies were complemented by metabolic analysis of mitochondrial function, lactic acid production, glucose consumption and ATP production.RESULTSThe data provide evidence to suggest that there are alternative pathways to the production of lactic acid outside of LDH conversion of pyruvate to lactic acid. The transcriptome analysis shows specific genes that could be involved with an alternative route of lactic acid production in cancer cells.DISCUSSION/CONCLUSIONThere is clearly enough evidence to suggest that acidity drives malignant processes using lactic acid as a means to control pH. Prevention of lactic acid production would be a formidable detriment to survival and metastasis of human malignancies, including TNBC.Support or Funding InformationNIH 2U54MD00758234A1