ORIGINAL RESEARCH published: 14 January 2020 doi: 10.3389/fonc.2019.01536 Frontiers in Oncology | www.frontiersin.org 1 January 2020 | Volume 9 | Article 1536 Edited by: Paolo E. Porporato, University of Turin, Italy Reviewed by: Pierre Sonveaux, Catholic University of Louvain, Belgium Fatima Baltazar, University of Minho, Portugal *Correspondence: Iñigo San-Millán inigo.sanmillan@cuanschutz.edu Specialty section: This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology Received: 26 October 2019 Accepted: 19 December 2019 Published: 14 January 2020 Citation: San-Millán I, Julian CG, Matarazzo C, Martinez J and Brooks GA (2020) Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells. Front. Oncol. 9:1536. doi: 10.3389/fonc.2019.01536 Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells Iñigo San-Millán 1,2 *, Colleen G. Julian 3 , Christopher Matarazzo 3 , Janel Martinez 1 and George A. Brooks 4 1 Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, United States, 2 Department of Human Physiology and Nutrition, University of Colorado, Colorado Springs, CO, United States, 3 Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States, 4 Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States Lactate is a ubiquitous molecule in cancer. In this exploratory study, our aim was to test the hypothesis that lactate could function as an oncometabolite by evaluating whether lactate exposure modifies the expression of oncogenes, or genes encoding transcription factors, cell division, and cell proliferation in MCF7 cells, a human breast cancer cell line. Gene transcription was compared between MCF7 cells incubated in (a) glucose/glutamine-free media (control), (b) glucose-containing media to stimulate endogenous lactate production (replicating some of the original Warburg studies), and (c) glucose-containing media supplemented with L-lactate (10 and 20 mM). We found that both endogenous, glucose-derived lactate and exogenous, lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B) (0.001 < p < 0.05 for all genes). Our findings support the hypothesis that lactate acts as an oncometabolite in MCF7 cells. Further research is necessary on other cell lines and biopsy cultures to show generality of the findings and reveal the mechanisms by which dysregulated lactate metabolism could act as an oncometabolite in carcinogenesis. Keywords: lactate, cancer, oncogenes, transcription factors, cell cycle genes INTRODUCTION A role of lactate in cancer metabolism was first described almost a century ago when Otto Warburg and associates discovered that cancer cells were not only characterized by accelerated glucose consumption, but also by a marked increase in lactate production (1). They exposed tumor cells to amino acids, fatty acids, and glucose, expecting the highest rate of respiration in glucose-exposed