Apr 8, 2020

The Harsh Microenvironment in Early Breast Cancer Select for a Warburg Phenotype

BioRxiv : the Preprint Server for Biology
M. DamaghiRobert J Gillies

Abstract

The harsh microenvironment of ductal carcinoma in situ (DCIS) exerts strong evolutionary selection pressures on cancer cells. We hypothesize that the poor metabolic conditions near the ductal center foment the emergence of a Warburg Effect (WE) phenotype, wherein cells rapidly ferment glucose to lactic acid, even in normoxia. To test this hypothesis, we subjected pre-malignant breast cancer cells to different microenvironmental selection pressures using combinations of hypoxia, acidosis, low glucose, and starvation for many months, and isolated single clones for metabolic and transcriptomic profiling. The two harshest conditions selected for constitutively expressed WE phenotypes. RNA-seq analysis of WE clones identified the transcription factors NFkB and KLF4 as potential inducers of the WE phenotype. NFkB was highly phosphorylated in the glycolytic clones. In stained DCIS samples, KLF4 expression was enriched in the area with the harshest microenvironmental conditions. We simulated in vivo DCIS phenotypic evolution using a mathematical model calibrated from the in vitro results. The WE phenotype emerged in the poor metabolic conditions near the necrotic core. We propose that harsh microenvironments within DCIS select for a Wa...Continue Reading

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Mentioned in this Paper

Genetic Drift
Biochemical Pathway
Nonhuman primate
Genome
Regulatory Sequences, Ribonucleic Acid
Genomic Stability
Pan troglodytes
Genomics
Cell Growth
Gene Regulatory Networks

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