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• W3015463745 abstract "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 NFкB and KLF4 as potential inducers of the WE phenotype. NFкB 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 Warburg phenotype through constitutive transcriptional reprogramming, thus conferring a survival advantage and facilitating further growth and invasion." @default.
• W3015463745 created "2020-04-17" @default.
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• W3015463745 date "2020-04-08" @default.
• W3015463745 modified "2023-09-30" @default.
• W3015463745 title "The Harsh Microenvironment in Early Breast Cancer Selects for a Warburg Phenotype" @default.
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• W3015463745 doi "https://doi.org/10.1101/2020.04.07.029975" @default.
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