Cited by 248Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismMetabolism, Diabetes, and Cancer

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Metabolic reprogramming in triple-negative breast cancer

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Wang, Zhanyu, Jiang, Qianjin, Dong, Chenfang·2020·Cancer Biology and Medicine

DOI 10.20892/j.issn.2095-3941.2019.0210PMC PMC7142847

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Abstract

Since triple-negative breast cancer (TNBC) was first defined over a decade ago, increasing studies have focused on its genetic and molecular characteristics. Patients diagnosed with TNBC, compared to those diagnosed with other breast cancer subtypes, have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment. Metabolic reprogramming, an emerging hallmark of cancer, is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands; maintain the redox balance; and further promote oncogenic signaling, cell proliferation, and metastasis. Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC. Here, we review the metabolic reprogramming of glycolysis, oxidative phosphorylation, amino acid metabolism, lipid metabolism, and other branched pathways in TNBC and explore opportunities for new biomarkers, imaging modalities, and metabolically targeted therapies.

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Figure 1 Metabolic reprogramming in triple-negative breast cancer (TNBC). TNBC upregulates several key glycolytic enzymes and transporters such as GLUT, HK, LDH, and MCT, therefore displaying high rate of glycolysis and glycolytic branched pathways, including serine synthesis and pentose phosphate pathway (PPP) for NADPH generation, and hexosamine biosynthetic pathway (HBP) for protein glycosylation. Other pathways such as fatty acid oxidation (FAO), glutaminolysis and cystine uptake are also induced in TNBC to meet its bioenergetic or biosynthetic demands, and mitigate reactive oxygen species (ROS) that is generated from oxidative phosphorylation (OXPHOS). Enzymes that are upregulated in TNBC are shown as light-yellow ovals, and enzymes downregulated in TNBC are shown as gray ovals.CC BY · PubMed Central

Figure 2 Switchable metabolic dependence on glycolysis and oxidative phosphorylation (OXPHOS) regulated by HIF-1α and AMPK. Under normoxic condition, HIF-1α is hydroxylated and subsequently degraded by PHD2 in an α-KG- and cysteine-dependent manner. In TNBC, decreased levels of α-KG and cysteine due to altered activity of transketolase (TKT) and xCT cystine/glutamate antiporter, respectively, contribute to normoxic activation of HIF-1α signaling, which triggers aerobic glycolysis with the upregulation of glycolysis-related enzymes and transporters. Although TNBC cells rely on glycolysis for rapid proliferation, OXPHOS which generate ATP more efficiently is also required, especially under bioenergetic stress. Activated AMPK and Myc pathways induce mitochondrial biogenesis and enzymes involved in glutaminolysis and fatty acid oxidation (FAO) to facilitate OXPHOS, thus endowing TNBC with metabolic plasticity to switch between glycolysis and OXPHOS. In addition, AMPK signaling also promotes epithelial-mesenchymal transition (EMT) through regulating lipid metabolism and increases the secretion of cytokines to recruit immunosuppressive myeloid-derived suppressor cells (MDSCs). Many drugs have been developed to target these key processes in the metabolic reprogramming of TNBC.CC BY · PubMed Central

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1 retracted

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Background
Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer
Dasgupta, S., Rajapakshe, K., Zhu, B., Nikolai, B. C., Yi, P., Putluri, N., Choi, J. M., Jung, S. Y., Coarfa, C., Westbrook, T. F., et al. (2018) · Nature · doi:10.1038/s41586-018-0018-1 · Cited by 252 · cited 1×
“…oncogenic steroid receptor coactivator-3 (Src-3) and enhances its transcriptional activity, which leads to the upregulation of transketolase (TKT), a major enzyme that mediates the non-oxidative pentose phosphate pathway (PPP), thus shunting glycolytic flux into the PPP for purine synthesis 22 .”
Background
Using the “reverse Warburg effect” to identify high-risk breast cancer patients: Stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers
Witkiewicz, A. K., Whitaker-Menezes, D., Dasgupta, A., Philp, N. J., Lin, Z., Gandara, R., Sneddon, S., Martinez-Outschoorn, U. E., Sotgia, F., & Lisanti, M. P. (2012) · Cell Cycle · doi:10.4161/cc.11.6.19530 · Cited by 239
Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications
Gandhi, N. S., & Das, G. M. (2019) · Cells · doi:10.3390/cells8020089 · Cited by 237 · cited 1×
“The tumor microenvironment and the different cells in this microenvironment are often modified by the dysregulated metabolism of tumor cells to further facilitate tumor growth in a symbiotic manner 131-133 .”
Background
Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine
Briggs, K. J., Koivunen, P., Cao, S., Backus, K. M., Olenchock, B. A., Patel, H., Zhang, Q. H., Signoretti, S., Gerfen, G. J., Richardson, A. L., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.042 · Cited by 228 · cited 1×
“Subsequently, the depletion of intracellular cysteine disables PHD2, which hydroxylates HIF-1 α for degradation, thus leading to the induction of HIF-1 α signaling and triple-negative breast carcinogenesis 44 ( Figure 2 ).”
Background
Microbiome—Microbial Metabolome—Cancer Cell Interactions in Breast Cancer—Familiar, but Unexplored
Mikó, E., Kovàcs, T., Sebő, É., Tóth, J., Csonka, T., Ujlaki, G., Sipos, A., Szabó, J., Méhes, G., & Bai, P. (2019) · Cells · doi:10.3390/cells8040293 · Cited by 228 · cited 1×
“Dysbiosis of the microbiome and microbial metabolome also plays a role in breast cancer metabolism and progression 134 .”
Background
Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways
Onodera, Y., Nam, J., & Bissell, M. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci63146 · Cited by 213 · cited 1×
“In contrast, decreasing glucose uptake in breast cancer cells suppresses these oncogenic pathways and promotes the formation of organized structures 20 .”
Background
Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP
Shen, L., O’Shea, J. M., Kaadige, M. R., Cunha, S., Wilde, B. R., Cohen, A. L., Welm, A. L., & Ayer, D. E. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1501555112 · Cited by 212 · cited 1×
“…genes, including LDH-A, pyruvate dehydrogenase kinase (PDK), and glutaminase (GLS) 18 ( Figure 2 ). c-Myc also represses the level of thioredoxin-interacting protein, a potent negative regulator of glucose uptake and glycolytic gene expression, to further activate aerobic glycolysis 19 .”
Background
CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation
Wright, H. J., Hou, J., Xu, B., Cortez, M., Potma, E. O., Tromberg, B. J., & Razorenova, O. V. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1703791114 · Cited by 211
Role of ferritin alterations in human breast cancer cells
Shpyleva, S., Tryndyak, V., Kovalchuk, O., Starlard‐Davenport, A., Chekhun, V. F., Beland, F. A., & Pogribny, I. P. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0849-4 · Cited by 205 · cited 1×
“Some TNBC cell lines show aberrantly increased heavy subunits of ferritin in the nucleus, where it can act as a GSH-independent anti-oxidative system, protecting the DNA from damage by oxidizing Fe 2+ to Fe 3+ to mitigate ROS stress after exposure to UV 99,100 .”
Background
Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer
Brown, K. K., Spinelli, J. B., Asara, J. M., & Toker, A. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0611 · Cited by 198 · cited 2×
“Exposure to doxorubicin likely stimulates pyrimidine synthesis by regulating the post-translational modification of CAD and its activity, whereas inhibiting DHODH sensitizes TNBC cells to doxorubicin and significantly induces the regression of TNBC xenografts 115 .”
Background
An Integrated Genomic Screen Identifies LDHB as an Essential Gene for Triple-Negative Breast Cancer
McCleland, M. L., Adler, A. S., Shang, Y., Hunsaker, T., Truong, T., Peterson, D., Torres, E., Li, L., Haley, B., Stéphan, J.-P., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1098 · Cited by 195 · cited 2×
“Enzymes that are upregulated in TNBC are shown as light-yellow ovals, and enzymes downregulated in TNBC are shown as gray ovals. tumor microenvironment 9,11 .”
Background
Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells
Hasegawa, M., Takahashi, H., Rajabi, H. N., Alam, M., Suzuki, Y., Li, Y., Tagde, A., Maeda, T., Hiraki, M., Sukhatme, V. P., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.7598 · Cited by 189 · cited 1×
“Meanwhile, mucin 1 (MUC1), a transmembrane glycoprotein that is aberrantly overexpressed in TNBC, binds directly to the intracellular domain of CD44v and further promotes the stability of xCT 43 .”
Background
Glutaminase is essential for the growth of triple-negative breast cancer cells with a deregulated glutamine metabolism pathway and its suppression synergizes with mTOR inhibition
Lampa, M., Arlt, H., He, T., Ospina, B., Reeves, J., Zhang, B., Murtie, J. C., Deng, G., Barberis, C., Hoffmann, D., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185092 · Cited by 172 · cited 12×
“Compared with other breast cancer subtypes, TNBC is more glutamine dependent and susceptible to glutaminolysis-targeting therapeutics because of the overexpression of GLS 30,31 , which is associated with high-grade metastatic breast cancer 32 .”
BackgroundInfluential
High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation
Antalis, C. J., Arnold, T. S., Rasool, T., Lee, B., Buhman, K. K., & Siddiqui, R. A. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0594-8 · Cited by 169 · cited 1×
“Meanwhile, elevated activity of low-density lipoprotein (LDL), caveolin-1, and cholesterol acyltransferase 1 (ACAT1) in TNBC is associated with greater uptake and utilization of cholesterol 87 .”
Background
Metabolic characterization of triple negative breast cancer
Cao, M. D., Lamichhane, S., Lundgren, S., Bofin, A. M., Fjøsne, H. E., Giskeødegård, G. F., & Bathen, T. F. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-941 · Cited by 165 · cited 1×
“Metabolomics analysis also reveals a low level of glutamine and a high level of glutamate in TNBC, indicating enhanced glutaminolysis 29 .”
Background
Association of FABP5 Expression With Poor Survival in Triple-Negative Breast Cancer
Liu, R., Graham, K., Glubrecht, D. D., Germain, D. R., Mackey, J. R., & Godbout, R. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.11.075 · Cited by 163 · cited 1×
“They promote cell proliferation by enhancing fatty acid uptake and activating the retinoic acid pathway 84,85 .”
Background
AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program
Wu, X., Li, X., Fu, Q., Cao, Q., Chen, X., Wang, M., Yu, J. Z., Long, J., Yao, J., Liu, H., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160903 · Cited by 157 · cited 2×
“…1 member B1 (AKR1B1) is activated in TNBC by Twist2, an inducer of EMT, and the accumulation of its major metabolite PGF2 α , in turn, activates NF-κ B signaling to upregulate Twist2 expression, which eventually forms a positive feedback loop to enhance the CSC properties in TNBC 88 ( Figure 2 ).”
Background
PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2
German, N. J., Yoon, H., Yusuf, R. Z., Murphy, J. P., Finley, L. W. S., Laurent, G., Haas, W., Satterstrom, F. K., Guarnerio, J., Zaganjor, E., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.08.014 · Cited by 156 · cited 14×
“Myc-overexpressing TNBC shows upregulated CPT activity and increased bioenergetic reliance on FAO through targeted metabolomics analysis 74 .”
BackgroundInfluential
GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity
Louie, S. M., Grossman, E. A., Crawford, L. A., Ding, L., Camarda, R., Huffman, T. R., Miyamoto, D. K., Goga, A., Weerapana, E., & Nomura, D. K. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2016.03.017 · Cited by 149 · cited 1×
“This energy reduction ultimately blocks oncogenic signaling through the activation of AMPK and the inhibition of mTOR signaling 21 .”
Background
RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation
Jones, R. A., Robinson, T., Liu, J. C., Shrestha, M., Voisin, V., Ju, Y., Chung, P. E. D., Pellecchia, G., Fell, V. L., Bae, S., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci81568 · Cited by 148 · cited 1×
“In addition, loss of the tumor-suppressor retinoblastoma gene ( RB1 ) in TNBC induces mitochondrial protein translation, OXPHOS, and anabolic metabolism, thus equipping cancer cells to utilize scant oxygen levels and migrate away from the hypoxic area 108,109 .”
Background
Mitochondrial OXPHOS Induced by RB1 Deficiency in Breast Cancer: Implications for Anabolic Metabolism, Stemness, and Metastasis
Zacksenhaus, E., Shrestha, M., Liu, J. C., Vorobieva, I., Chung, P. E. D., Ju, Y., Nir, U., & Jiang, Z. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.09.002 · Cited by 143 · cited 1×
“In addition, loss of the tumor-suppressor retinoblastoma gene ( RB1 ) in TNBC induces mitochondrial protein translation, OXPHOS, and anabolic metabolism, thus equipping cancer cells to utilize scant oxygen levels and migrate away from the hypoxic area 108,109 .”
Background
S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer
Switzer, C. H., Glynn, S. A., Cheng, R. Y.-S., Ridnour, L. A., Green, J. E., Ambs, S., & Wink, D. A. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0124 · Cited by 141
The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours
Ansari, R. E., Craze, M. L., Miligy, I. M., Diez, M., Nolan, C. C., Ellis, I. O., Rakha, E. A., & Green, A. R. (2018) · Breast Cancer Research · doi:10.1186/s13058-018-0946-6 · Cited by 140
PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition
Mathur, D., Stratikopoulos, E., Ozturk, S., Steinbach, N., Pegno, S., Schoenfeld, S., Yong, R., Murty, V. V., Asara, J. M., Cantley, L. C., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0612 · Cited by 139 · cited 2×
“Moreover, leflunomide induces the depletion of nucleotides and the accumulation of DNA damage during replication, leading to synthetic lethality in TNBC cells with the loss of PTEN, which is vital for DNA repair activity 116 .”
Background
Transketolase Regulates the Metabolic Switch to Control Breast Cancer Cell Metastasis via the α-Ketoglutarate Signaling Pathway
Tseng, C.-W., Kuo, W., Chan, S., Chan, H., Chang, K., & Wang, L. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2906 · Cited by 131
Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer
Lanzardo, S., Conti, L., Rooke, R., Ruiu, R., Accart, N., Bolli, E., Arigoni, M., Macagno, M., Barrera, G., Pizzimenti, S., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1208 · Cited by 130 · cited 2×
“Silencing of xCT impairs tumorsphere formation and the redox balance in breast cancer stem cells (BCSCs) 31,40 .”
Background
Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling
Gautam, J., Banskota, S., Regmi, S. C., Ahn, S., Jeon, Y. H., Jeong, H., Kim, S. J., Nam, T. G., Jeong, B., & Kim, J. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0559-6 · Cited by 128
Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers
Witkiewicz, A. K., Dasgupta, A., Sammons, S., Er, O. S., Potoczek, M., Guiles, F., Sotgia, F., Brody, J. R., Mitchell, E. P., & Lisanti, M. P. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.2.11983 · Cited by 127 · cited 1×
“The tumor microenvironment and the different cells in this microenvironment are often modified by the dysregulated metabolism of tumor cells to further facilitate tumor growth in a symbiotic manner 131-133 .”
Background
18F-Fluorodeoxy-glucose Positron Emission Tomography Marks MYC-Overexpressing Human Basal-Like Breast Cancers
Palaskas, N. J., Larson, S. M., Schultz, N. D., Komisopoulou, E., Wong, J., Rohle, D., Campos, C., Yannuzzi, N. A., Osborne, J. R., Linkov, I., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4633 · Cited by 126 · cited 12×
“Compared with other breast cancer subtypes, TNBC is more glutamine dependent and susceptible to glutaminolysis-targeting therapeutics because of the overexpression of GLS 30,31 , which is associated with high-grade metastatic breast cancer 32 .”
BackgroundInfluential
Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer
Speyer, C. L., Smith, J. S., Banda, M., DeVries, J. A., Mekani, T., & Gorski, D. H. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-011-1624-x · Cited by 122
Nitric Oxide Modifies Global Histone Methylation by Inhibiting Jumonji C Domain-containing Demethylases
Hickok, J. R., Vasudevan, D., Antholine, W. E., & Thomas, D. D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.432294 · Cited by 120 · cited 1×
“In addition, NO can directly inhibit the catalytic activity of the demethylase KDM3A; thereby, it alters cellular histone methylation patterns 67 , leading to changes in the expression levels of numerous oncogenes such as Ets-1 68 .”
Background
Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome
Doyen, J., Trastour, C., Ettore, F., Peyrottes, I., Toussant, N., Gal, J., Ilc, K., Roux, D., Parks, S. K., Ferrero, J.-M., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.07.050 · Cited by 116 · cited 1×
“Enzymes that are upregulated in TNBC are shown as light-yellow ovals, and enzymes downregulated in TNBC are shown as gray ovals. tumor microenvironment 9,11 .”
Background
Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression
Strekalova, E., Malin, D., Good, D. M., & Cryns, V. L. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2792 · Cited by 107 · cited 2×
“The depletion of either methionine or glutamine can increase the cell surface expression of pro-apoptotic TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) and sensitize TNBC cells to TRAIL-induced apoptosis 71,72 .”
Background
Targeting lactate transport suppressesin vivobreast tumour growth
Morais-Santos, F., Granja, S., Miranda‐Gonçalves, V., Moreira, A. H. J., Queirós, S., Vilaça, J. L., Schmitt, F. C., Longatto‐Filho, A., Paredes, J., Baltazar, F., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3910 · Cited by 105 · cited 1×
“Disruption of lactate transport impairs tumor growth in vitro and in vivo , accompanied by reduced tumor aggressiveness 12 .”
Background
Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b
Wahdan-Alaswad, R. S., Cochrane, D. R., Spoelstra, N. S., Howe, E. N., Edgerton, S. M., Anderson, S. M., Thor, A. D., & Richer, J. K. (2014) · Hormones and Cancer · doi:10.1007/s12672-014-0188-8 · Cited by 104 · cited 1×
“Nevertheless, blocking FASN and lipogenesis by metformin or EGCG also induces antitumor effects on TNBC 81,82 , suggesting an intricate role of FAS in cancer cells.”
Background
Caloric restriction augments radiation efficacy in breast cancer
Saleh, A. D., Simone, B. A., Palazzo, J., Savage, J. E., Sano, Y., Dan, T., Jin, L., Champ, C. E., Zhao, S., Lim, M. K., et al. (2013) · Cell Cycle · doi:10.4161/cc.25016 · Cited by 103 · cited 1×
“Other dietary modifications, such as caloric restriction, also cause tumor regression in combination with radiation 130 .”
Tumor LDH-A expression and serum LDH status are two metabolic predictors for triple negative breast cancer brain metastasis
Dong, T., Liu, Z., Xuan, Q., Wang, Z., Ma, W., & Zhang, Q. (2017) · Scientific Reports · doi:10.1038/s41598-017-06378-7 · Cited by 101 · cited 1×
“Either tumoral LDH-A or LDH-B is closely associated with poor clinical outcomes in patients with TNBC 9,10 .”
Background
[18F](2 S ,4 R )4-Fluoroglutamine PET Detects Glutamine Pool Size Changes in Triple-Negative Breast Cancer in Response to Glutaminase Inhibition
Zhou, R., Pantel, A. R., Li, S., Lieberman, B. P., Plöessl, K., Choi, H., Blankemeyer, E. R., Lee, H. S., Kung, H. F., Mach, R. H., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-1945 · Cited by 99
Glutaminase isoenzymes in the metabolic therapy of cancer
Matés, J. M., Campos-Sandoval, J. A., & Márquez, J. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.007 · Cited by 99 · cited 1×
“Several small-molecule inhibitors of GLS, such as CB-839, BPTES, and compound 968 33 normoxic condition, HIF-1 α is hydroxylated and subsequently degraded by PHD2 in an α -KG- and cysteine-dependent manner.”
Background
Prognostic relevance of glycosylation-associated genes in breast cancer
Milde‐Langosch, K., Karn, T., Schmidt, M., zu Eulenburg, C., Oliveira‐Ferrer, L., Wirtz, R. M., Schumacher, U., Witzel, I., Schütze, D., & Müller, V. (2014) · Breast Cancer Research and Treatment · doi:10.1007/s10549-014-2949-z · Cited by 98 · cited 1×
“Dysregulation of protein glycosylation, resulting from an increased flux of the hexosamine biosynthetic pathway (HBP), contributes to breast tumor progression or metastasis 113 .”
Background
Methionine deprivation suppresses triple-negative breast cancer metastasisin vitroandin vivo
Jeon, H., Kim, J. H., Lee, E., Jang, Y. J., Kwon, J. Y., Kwon, J. Y., Kim, S., Kim, S., Park, J. H. Y., Kim, J.-E., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11615 · Cited by 98 · cited 2×
“…methionine, and glutamine metabolism are also essential for modulating the metastasis, stemness, and apoptosis of TNBC. Dietary restriction or otherwise inhibiting the synthesis of these amino acids has tumor-suppressing effects, which is discussed later in the section of clinical practice 70-73 .”
Background
Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways
Garrido, P., Shalaby, A. M., Walsh, E. M., Keane, N., Webber, M., Keane, M., Sullivan, F. J., Kerin, M. J., Callagy, G. M., Ryan, A. E., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19631 · Cited by 93
2-Deoxy-D-Glucose inhibits aggressive triple-negative breast cancer cells by targeting glycolysis and the cancer stem cell phenotype
O’Neill, S., Porter, R. K., McNamee, N., Martinez, V. G., & O’Driscoll, L. (2019) · Scientific Reports · doi:10.1038/s41598-019-39789-9 · Cited by 93 · cited 1×
“…from OXPHOS to glycolysis, and glycolytic inhibitor can indeed significantly suppress the aggressiveness and CSC phenotype of TNBC cells 101 , it is noteworthy that inhibition of glycolysis also promotes the transition of BCSC in TNBC from a quiescent, mesenchymal-like state…”
Background
The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer
Thewes, V., Simon, R., Hlevnjak, M., Schlotter, M., Schroeter, P., Schmidt, K. V., Wu, Y., Anzeneder, T., Wang, W., Windisch, P. Y., et al. (2017) · Oncogene · doi:10.1038/onc.2017.32 · Cited by 90
Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer
Giró‐Perafita, A., Palomeras, S., Lum, D. H., Blancafort, A., Viñas, G., Oliveras, G., Pérez-Bueno, F., Sarrats, A., Welm, A. L., & Puig, T. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-3133 · Cited by 88
Inhibition of the Hexosamine Biosynthetic Pathway by targeting PGM3 causes breast cancer growth arrest and apoptosis
Ricciardiello, F., Votta, G., Palorini, R., Raccagni, I., Brunelli, L., Paiotta, A., Tinelli, F., D’Orazio, G., Valtorta, S., GIOIA, L. D., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0405-4 · Cited by 88 · cited 2×
“A novel inhibitor of the HBP enzyme PGM3, FR054, reduces both N-and O-glycosylation levels to regulate cell adhesion and migration, impairing tumor growth in vivo 114 .”
Background
Loss of GLUT4 Induces Metabolic Reprogramming and Impairs Viability of Breast Cancer Cells
Garrido, P., Osorio, F. G., Morán, J., Cabello, E., Alonso, A., Freije, J. M. P., & González, C. (2014) · Journal of Cellular Physiology · doi:10.1002/jcp.24698 · Cited by 87 · cited 1×
“Knocking down GLUT4 diminishes glucose uptake and lactate release, thus normalizing the metabolism of cancer by reallocating the glycolytic flux to OXPHOS, which leads to compromised cell proliferation and viability under hypoxia 8 .”
Background
Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling
Tang, X., Ding, C.-K., Wu, J., Sjol, J., Wardell, S. E., Spasojević, I., George, D. J., McDonnell, D. P., Hsu, D. S., Chang, J. T., et al. (2016) · Oncogene · doi:10.1038/onc.2016.394 · Cited by 86 · cited 1×
“…starvation induces mitochondrial fragmentation and ROS production, leading to necroptosis and ferroptosis in BLBC cells via the tumor necrosis factor alpha (TNF α ) and MEKK4-p38-Noxa pathways, while luminal-type breast cancer, without activation of these pathways, is cystine independent 48,49 .”
Background
S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells
Strekalova, E., Malin, D., Weisenhorn, E., Russell, J. D., Hoelper, D., Jain, A. Y., Coon, J. J., Lewis, P. W., & Cryns, V. L. (2019) · Breast Cancer Research and Treatment · doi:10.1007/s10549-019-05146-7 · Cited by 85 · cited 1×
“Limiting dietary methionine induces MAT2A expression in TNBC as an adaptive response; therefore, the combination of methionine restriction and the MAT2A inhibitor cycloleucine has a synergistic antitumor effect 128 .”
Background
Characterization of the interactions of potent allosteric inhibitors with glutaminase C, a key enzyme in cancer cell glutamine metabolism
Huang, Q., Stalnecker, C. A., Zhang, C., McDermott, L. A., Iyer, P. C., O’Neill, J., Reimer, S., Cerione, R. A., & Katt, W. P. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.810101 · Cited by 83 · cited 1×
“Other combination therapies, such as the combination of GLS inhibition and bevacizumab (an anti-angiogenesis monoclonal antibody that targets VEGF), also exhibit antitumor effects on TNBC 124 .”
Background
High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis
Avanzato, D., Pupo, E., Ducano, N., Isella, C., Bertalot, G., Luise, C., Pece, S., Bruna, A., Rueda, O. M., Caldas, C., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3018 · Cited by 82 · cited 1×
“The EGFR signaling, frequently active in TNBC, triggers the expression of hexokinase 2 (HK2) and stabilizes GLUT1 on the cell membrane 13 , whereas it reduces the activity of PKM2 14 , thus causing an accumulation of the glycolytic intermediate, fructose-1,6-bisphosphate (F-1,6-BP).”
Background
Metabolic changes associated with methionine stress sensitivity in MDA-MB-468 breast cancer cells
Borrego, S. L., Fahrmann, J. F., Datta, R., Stringari, C., Grapov, D., Zeller, M. D., Chen, Y., Wang, P., Baldi, P., Gratton, E., et al. (2016) · Cancer & Metabolism · doi:10.1186/s40170-016-0148-6 · Cited by 77 · cited 1×
“Additionally, many tumor and stem cells depend on the biosynthesis of the universal methyl-donor S-adenosylmethionine (SAM) from exogenous methionine by methionine adenosyltransferase 2 α (MAT2A) to maintain their epigenome 126,127 .”
Background
Serine Synthesis Helps Hypoxic Cancer Stem Cells Regulate Redox
Samanta, D., & Semenza, G. L. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1730 · Cited by 76 · cited 1×
“Phosphoglycerate dehydrogenase (PHGDH), as a key enzyme in the first step of serine synthesis, is overexpressed in both TNBC and BLBC, in part, because of copy number amplification 50,51 .”
Background
NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer
Hong, S.-P., Cw, P., Kim, S. W., Nam, Y. J., Yu, J. H., Shin, J. H., Yun, C. H., Im, S., Kim, K.-T., Sung, Y. C., et al. (2015) · Oncogene · doi:10.1038/onc.2015.415 · Cited by 74 · cited 2×
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Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis
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Lipin‐1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple‐negative breast cancer cell survival
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Identification of Biomarkers Including 18FDG-PET/CT for Early Prediction of Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer
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Background
A fatty acid‐binding protein 7/RXRβ pathway enhances survival and proliferation in triple‐negative breast cancer
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Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression
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Background
Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells
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Nitric Oxide Regulates Gene Expression in Cancers by Controlling Histone Posttranslational Modifications
Vasudevan, D., Hickok, J. R., Bovee, R. C., Pham, V., Mantell, L. L., Bahroos, N., Kanabar, P. N., Cao, X.-J., Maienschein‐Cline, M., Garcia, B. A., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1582 · Cited by 67 · cited 1×
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Deciphering metabolic rewiring in breast cancer subtypes
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Background
Metabotropic Glutamate Receptor-1 as a Novel Target for the Antiangiogenic Treatment of Breast Cancer
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A Virus-Like-Particle immunotherapy targeting Epitope-Specific anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancerin vivo
Bolli, E., O’Rourke, J. P., Conti, L., Lanzardo, S., Rolih, V., Christen, J. M., Barutello, G., Forni, M., Pericle, F., & Cavallo, F. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1408746 · Cited by 66 · cited 1×
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“Energetic” Cancer Stem Cells (e-CSCs): A New Hyper-Metabolic and Proliferative Tumor Cell Phenotype, Driven by Mitochondrial Energy
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Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca2+-NFAT1 Axis
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ME1 promotes basal-like breast cancer progression and associates with poor prognosis
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Background
Repression of phosphoglycerate dehydrogenase sensitizes triple-negative breast cancer to doxorubicin
Zhang, X., & Bai, W. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3117-4 · Cited by 54 · cited 1×
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Review of Triple Negative Breast Cancer and the Impact of Inducible Nitric Oxide Synthase on Tumor Biology and Patient Outcomes
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Distinct breast cancer stem/progenitor cell populations require either HIF1α or loss of PHD3 to expand under hypoxic conditions
Iriondo, O., Rábano, M., Domenici, G., Carlevaris, O., López-Ruiz, J. A., Zabalza, I., Berra, E., & Vivanco, M. D. (2015) · Oncotarget · doi:10.18632/oncotarget.5564 · Cited by 52
The isomiR-140-3p-regulated mevalonic acid pathway as a potential target for prevention of triple negative breast cancer
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Argininosuccinate lyase is a potential therapeutic target in breast cancer
Huang, H.-L., Chen, W.-C., Hsu, H., Cho, C.-Y., Hung, Y.-H., Wang, C., & Lai, M.-D. (2015) · Oncology Reports · doi:10.3892/or.2015.4280 · Cited by 49 · cited 1×
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Background
Metabolic targeting of breast cancer cells with the 2-deoxy-D-glucose and the mitochondrial bioenergetics inhibitor MDIVI-1
Lucantoni, F., Dussmann, H., & Prehn, J. H. M. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00113 · Cited by 47 · cited 1×
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Background
Preventing BRCA 1/ ZBRK 1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation
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Background
Mapping Metabolic Events in the Cancer Cell Cycle Reveals Arginine Catabolism in the Committed SG2M Phase
Roçi, I., Watrous, J. D., Lagerborg, K. A., Lafranchi, L., Lindqvist, A., Jain, M., & Nilsson, R. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.059 · Cited by 44
Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers
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“For example, in response to T cell-derived interferon (IFN)- γ , TNBC exhibits highly inducible expression of IDO1 to counteract immune cells 57 ( Figure 2 ).”
Background
Glutaminase expression is a poor prognostic factor in node-positive triple-negative breast cancer patients with a high level of tumor-infiltrating lymphocytes
Kim, J. Y., Heo, S., Choi, S. K., Song, I. H., Park, I. A., Kim, Y., Park, H. S., Park, S. Y., Bang, W. S., Gong, G., et al. (2017) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-017-2083-5 · Cited by 36 · cited 1×
“…of tumor-infiltrating lymphocytes (TILs), suggesting a metabolic competition between cancer cells and TILs in the tumor microenvironment, where active consumption of intercellular glutamine by GLS-overexpressing TNBC cells deprives TILs of glutamine and hinders their proliferation 34 ( Figure 2 ).”
Background
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells
Mauro-Lizcano, M., & López‐Rivas, A. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0263-0 · Cited by 33 · cited 1×
“The depletion of either methionine or glutamine can increase the cell surface expression of pro-apoptotic TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) and sensitize TNBC cells to TRAIL-induced apoptosis 71,72 .”
Background
Glutamate-Weighted Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Detects Glutaminase Inhibition in a Mouse Model of Triple-Negative Breast Cancer
Zhou, R., Bagga, P., Nath, K., Hariharan, H., Mankoff, D. A., & Reddy, R. D. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3988 · Cited by 27 · cited 1×
“Similar to MRS, these methods enable the observation of altered levels of glutamine or glutamate upon GLS inhibition, indicating their feasibility to non-invasively detect the early therapeutic response of TNBC to GLS inhibitors 120,121 .”
Result
Hallmarks of the cancer cell of origin: Comparisons with “energetic” cancer stem cells (e-CSCs)
Sotgia, F., Fiorillo, M., & Lisanti, M. P. (2019) · Aging · doi:10.18632/aging.101822 · Cited by 26 · cited 1×
“Epithelial-like BCSCs exhibit elevated OXPHOS coupled with the upregulation of GSH metabolism and anti-oxidant defense 102 , which is also observed in “energetic” cancer stem cells (e-CSCs) and TNBC brain or lung metastases 103-106 .”
Background
Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer
Sexton, R. E., Hachem, A. H., Assi, A. A., Bukhsh, M. A., Gorski, D. H., & Speyer, C. L. (2018) · Scientific Reports · doi:10.1038/s41598-018-34502-8 · Cited by 25 · cited 1×
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Background
Effect of Rosuvastatin on Arginase Enzyme Activity and Polyamine Production in Experimental Breast Cancer
Erbaş, H., Bal, O., & Çakır, E. (2015) · Balkan Medical Journal · doi:10.5152/balkanmedj.2015.15611 · Cited by 20 · cited 1×
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Background
Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from 18F-FDG PET/CT in operable triple-negative breast cancer
Kim, Y., Kim, Y. J., Paeng, J. C., Cheon, G. J., Lee, D. S., Chung, J.-K., & Kang, K. W. (2017) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-017-3748-7 · Cited by 20
Untargeted and stable isotope-assisted metabolomic analysis of MDA-MB-231 cells under hypoxia
Yang, J., Cheng, J., Sun, B. H., Li, H., Wu, S., Dong, F., & Yan, X. (2018) · Metabolomics · doi:10.1007/s11306-018-1338-8 · Cited by 19 · cited 1×
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Background
[18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer
Raccagni, I., Belloli, S., Valtorta, S., Stefano, A., Presotto, L., Pascali, C., Bogni, A., Tortoreto, M., Zaffaroni, N., Daidone, M. G., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0197754 · Cited by 16 · cited 2×
“Neo-adjuvant chemotherapy based on anthracyclines and taxanes is increasingly used prior to surgery to reduce the size of unresectable TNBC. Traditionally, the response to chemotherapy is assessed by tumor volume, which represents a post-treatment event 117 .”
Background

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Authors: Wang, Z., Jiang, Q., & Dong, C.
Affiliations: Second Affiliated Hospital of Zhejiang University (CN)
Zhejiang University (CN)
Corresponding author: Dong, Chenfang
ORCID: Wang, Zhanyu
Dong, Chenfang
Venue: Cancer Biology and Medicine
Publisher: China Anti-cancer Association
Published: 2020
Volume: 17
Issue: 1
Pages: 44-59
ISSN: 2095-3941 (ISSN-L)
DOI: 10.20892/j.issn.2095-3941.2019.0210
PMC: PMC7142847
OpenAlex: W3020548503
Cited by: 248
References: 135
Citations by year: 2026: 61 · 2025: 63 · 2024: 46 · 2023: 31 · 2022: 20 · 2021: 18 · 2020: 8
FWCI: 6.58
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Cancer Biology and Medicine (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: triple-negative breast cancer, metabolic reprogramming, glycolysis, oxidative phosphorylation, amino acid metabolism, lipid metabolism, redox homeostasis, oncogenic signaling, metastasis, metabolic biomarkers, metabolic imaging
MeSH terms: Warburg Effect, Oncologic, Amino Acids, Antineoplastic Agents, Female, Humans, Oxidative Phosphorylation, Biomarkers, Tumor, Lipid Metabolism, Molecular Targeted Therapy, Triple Negative Breast Neoplasms

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Metabolic reprogramming in triple-negative breast cancer

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