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Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction

Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxi...

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Autores principales: Coleman, Michael F., O’Flanagan, Ciara H., Pfeil, Alexander J., Chen, Xuewen, Pearce, Jane B., Sumner, Susan, Krupenko, Sergey A., Hursting, Stephen D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152779/
https://www.ncbi.nlm.nih.gov/pubmed/34068120
http://dx.doi.org/10.3390/nu13051637
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author Coleman, Michael F.
O’Flanagan, Ciara H.
Pfeil, Alexander J.
Chen, Xuewen
Pearce, Jane B.
Sumner, Susan
Krupenko, Sergey A.
Hursting, Stephen D.
author_facet Coleman, Michael F.
O’Flanagan, Ciara H.
Pfeil, Alexander J.
Chen, Xuewen
Pearce, Jane B.
Sumner, Susan
Krupenko, Sergey A.
Hursting, Stephen D.
author_sort Coleman, Michael F.
collection PubMed
description Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.
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spelling pubmed-81527792021-05-27 Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction Coleman, Michael F. O’Flanagan, Ciara H. Pfeil, Alexander J. Chen, Xuewen Pearce, Jane B. Sumner, Susan Krupenko, Sergey A. Hursting, Stephen D. Nutrients Article Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy. MDPI 2021-05-13 /pmc/articles/PMC8152779/ /pubmed/34068120 http://dx.doi.org/10.3390/nu13051637 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Coleman, Michael F.
O’Flanagan, Ciara H.
Pfeil, Alexander J.
Chen, Xuewen
Pearce, Jane B.
Sumner, Susan
Krupenko, Sergey A.
Hursting, Stephen D.
Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title_full Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title_fullStr Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title_full_unstemmed Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title_short Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction
title_sort metabolic response of triple-negative breast cancer to folate restriction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152779/
https://www.ncbi.nlm.nih.gov/pubmed/34068120
http://dx.doi.org/10.3390/nu13051637
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