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Metabolic differences in breast cancer stem cells and differentiated progeny

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In general, tumor cells display a more glycolytic phenotype compared to the corresponding normal tissue. However, it is becoming increasingly clear that tumors are composed of a heterogeneous population of cells. Breast cancers are organized in a hierarchical manner, with the breast cancer stem cells (BCSCs) at the top of the hierarchy. Here, we investigate the metabolic phenotype of BCSCs and their differentiated progeny. In addition, we determine the effect of radiation on the metabolic state of these two cell populations. Luminal, basal, and claudin-low breast cancer cell lines were propagated as mammospheres enriched in BCSCs. Lactate production, glucose consumption, and ATP content were compared with differentiated cultures. A metabolic flux analyzer was used to determine the oxygen consumption, extracellular acidification rates, maximal mitochondria capacity, and mitochondrial proton leak. The effect of radiation treatment of the metabolic phenotype of each cell population was also determined. BCSCs consume more glucose, produce less lactate, and have higher ATP content compared to their differentiated progeny. BCSCs have higher maximum mitochondrial capacity and mitochondrial proton leak compared to their differentiated progeny. Radiation treatment enhances the higher energetic state of the BCSCs, while decreasing mitochondrial proton leak. Our study indicated that breast cancer cells are heterogeneous in their metabolic phenotypes and BCSCs reside in a distinct metabolic state compared to their differentiated progeny. BCSCs display a reliance on oxidative phosphorylation, while the more differentiated progeny displays a more glycolytic phenotype. Radiation treatment affects the metabolic state of BCSCs. We conclude that interfering with the metabolic requirements of BCSCs may prevent radiation-induced reprogramming of breast cancer cells during radiation therapy, thus improving treatment outcome.

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We would like to thank Ekaterini Angelis, PhD, for careful editing of this manuscript. FP was supported by a generous gift from Steve and Cathy Fink and by grants from the National Cancer Institute (1RO1CA137110, 1R01CA161294) and the Army Medical Research & Materiel Command’s Breast Cancer Research Program (W81XWH-11-1-0531). LV and KR were supported by S10RR026744 (National Center for Research Resources) and P01 HL028481 (National Institutes of Health).

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Correspondence to Frank Pajonk.

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Fig. S1

a Representative oxygen consumption rates measured as a function of time on a Seahorse platform, as different metabolic inhibitors are added to the cell media. b Several parameters were deducted from the changes in oxygen consumption (a), such as: basal OCR, maximum mitochondrial capacity, and mitochondrial reserve capacity (=[maximum mitochondrial capacity] − [basal OCR]) as described previously in [10]. BCSCs and non-tumorigenic cells did not differ in ATP turnover, mitochondrial reserve capacity, or non-mitochondrial respiration

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Vlashi, E., Lagadec, C., Vergnes, L. et al. Metabolic differences in breast cancer stem cells and differentiated progeny. Breast Cancer Res Treat 146, 525–534 (2014).

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