Role of Lactate in the Regulation of Transcriptional Activity of Breast Cancer-Related Genes and Epithelial-to-Mesenchymal Transition Proteins: A Comparison of MCF7 and MDA-MB-231 Cancer Cell Lines

The Warburg Effect is characterized by accelerated glycolytic metabolism and lactate production and is a hallmark of cancer cells. Recently, we have demonstrated the role of endogenous, glucose-derived lactate as an oncometabolite which regulates gene expression in the estrogen receptor positive (ER+) MCF7 cell line cultivated in glucose media (San-Millan, Julian et al. 2019). Presently, with the addition of a triple negative breast cancer (TNBC) cell line, MDA-MB-231, we further confirm the effect of lactate on gene expression patterns, but extend results to include lactate effects on protein expression. As well, we report effects of lactate on the expression of E-cadherin and vimentin, proteins associated with epithelial-to-mesenchymal transition (EMT). Endogenous lactate regulates the expression of multiple genes involved in carcinogenesis. In MCF7 cells, lactate increased the expression of EGFR, VEGF HIF-1a, KRAS, MIF, mTOR, PIK3CA, TP53, and CDK4 (The Ital is used for genes) as well as decreased the expression of ATM, BRCA1, BRCA2, E2F1, MET, MYC, and RAF mainly at 48h of exposure. On the other hand, in the MDA-MB-231 cell line, lactate increased the expression of PIK3CA, VEGF, EGFR, mTOR, HIF-1α, ATM, E2F1, TP53 and decreased the expression of BRCA1, BRCA2, CDK4, CDK6, MET, MIF, MYC, and RAF after 48h of exposure. Protein expression of representative genes corroborated mRNA expressions. Finally, lactate decreased E-cadherin protein expression in MCF7 cells and increased vimentin expression in MDA-MB-231 cells. In this study, we demonstrate that endogenous lactate produced under aerobic conditions (Warburg Effect) is capable of eliciting important regulation of gene and protein expression in both ER+ and TNBC cell lines. The regulation of multiple genes by lactate is widespread and involves those involved in carcinogenesis including DNA repair, cell growth, proliferation, angiogenesis, and metastasis. Furthermore, both cell lines demonstrated changes in the expression of EMT biomarkers representing a shift to a more mesenchymal phenotype with exposure to endogenous lactate. Simple Summary This study shows how endogenous lactate is a major regulator of key genes involved in two main breast cancer cell types: estrogen receptor positive (ER+) and triple negative breast cancer cells (TPBC). Lactate regulates both gene and protein expression in these cells. Furthermore, lactate is also an important player in the regulation of epithelial-to-mesenchymal transition (EMT), a process involved in metastasis. Targeting lactate production and exchange within and among cancer cells should offer novel therapeutics opportunities.