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Frontiers of Medicine

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ISSN 2095-0225(Online)

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Front. Med.    2021, Vol. 15 Issue (2) : 178-207    https://doi.org/10.1007/s11684-020-0793-6
REVIEW
Metabolism and immunity in breast cancer
Deyu Zhang, Xiaojie Xu(), Qinong Ye()
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China
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Abstract

Breast cancer is one of the most common malignancies that seriously threaten women’s health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host’s immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.
Keywords breast cancer      metabolism      immunity      cancer stem cells     
Corresponding Author(s): Xiaojie Xu,Qinong Ye   
Just Accepted Date: 31 August 2020   Online First Date: 20 October 2020    Issue Date: 23 April 2021
 Cite this article:   
Deyu Zhang,Xiaojie Xu,Qinong Ye. Metabolism and immunity in breast cancer[J]. Front. Med., 2021, 15(2): 178-207.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0793-6
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I2/178
Metabolism Specific classification of metabolism Level of metabolism in breast cancer Reference
Glycometabolism Glucose uptake Increase [35]
Warburg effect Increase [1]
TCA cycle Abnormal [1]
Pentose phosphate pathway Increase [36]
Gluconeogenesis Decrease [37]
Lipid metabolism Fatty acid uptake Uncertain but important [38]
De novo fatty acid synthesis Increase [39]
Fatty acid oxidation Increase [40]
Amino acid metabolism Glutamine metabolism Increase [41]
Serine and glycine metabolism Increase [42]
Cysteine metabolism Increase [42]
Arginine metabolism Uncertain [42]
Tab.1  Abnormal metabolism in breast cancer
Fig.1  Glucose metabolism. HK, PFK, and PK are the three key enzymes in glycolysis. G6PD regulates the rates of the PPP by catalyzing the oxidation. In general, pyruvate is oxidized into carbon dioxide and water in the mitochondria, which is catalyzed by three key enzymes, namely, CS, IDH, and KGDHC. Pyruvate is converted to lactate by LDHA in cancer cells, and lactate is expelled from the cell by MCT4. Gluconeogenesis can influence glycolysis, TCA, PPP, and other processes indirectly via the rates of glucose production. Three key enzymes control the gluconeogenic flux, including PEPCK, FBP, and G6PC. Abbreviations: G6P, glucose 6-phosphate; F6P, fructose 6-phoshate; F–1,6-bisP, fructose-1,6-bisphosphate; G3P, glyceraldehyde 3-phosphate; 1,3-PGA, 1,3-disphosphoglycerate; 3-PG, glyceraldeyde 3-phosphate; 2-PG, glyceraldeyde 2-phosphate; PEP, phosphoenolpyravate; TCA, tricarboxylic acid cycle; a-KG, a-ketoglutarate; GLUTs, glucose transporters; HK2, hexokinase 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PFK, 6-phosphofructo kinase; ALDO, aldolase; TPI, triose phosphate isomerase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; ENO1, enolase; PKM, pyruvate kinase; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; CS, citrate synthase; IDH, isocitrate dehydrogenase; KGDHC, a-ketoglutarate dehydrogenase complex; G6PD, glucose 6-phosphate dehydrogenase; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; FBP, fructose-1,6-bisphosphatase; G6PC, glucose-6-phosphatase.
Fig.2  Lipid metabolism. In the de novo fatty acid synthesis, citrate is catalyzed into FA by ACLY, ACC, and FASN sequentially. CD36 and FABPs are involved in the intake of FA. FA needs to be transformed to FA-CoA before they enter the subsequent metabolism, including anabolism or catabolism. During fatty acid b-oxidation, FA-CoA is transported into the mitochondria and then oxidized, the rate of which is limited by CPT1. FA-CoA and DAG are synthesized into TG catalyzed by DGAT. During triglyceride synthesis, the glycolytic intermediate 3-PG is converted into DAG by AGPT2 and lipin-1, and DAG is ultimately converted into TG. Abbreviations: ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; FABP, fatty acid binding protein; AGPAT2, acylglycerol-3-phosphate acyltransferase 2; CPT1, carnitine palmitoyltransferase 1; CIC, citrate carrier; FA, fatty acid; TG, triglyceride; DAG, diacylglycerol; 3-PG, glyceraldeyde 3-phosphate; DGAT, diacylglycerol acyltransferase; AGPAT2, acylglycerol-3-phosphate acyltransferase 2.
Fig.3  Amino acid metabolism. Glutamine uptake is regulated by SLC1A5, SLC7A5, and SLC7A11. Glutamine is converted into glutamate by GLS, and the counter-reaction is catalyzed by GS. GLUD catalyzes glutamate to a-KG. Glutamate is converted into alanine by ALT and converted into aspartic acid by AST. ASNS utilizes glutamine as a nitrogen donor to turn aspartic acid to asparagine. In addition, the glycolytic intermediate 3-PG is oxidized into serine catalyzed by PHGDH, PSAT1, and PSPH. Serine is converted into glycine by SHMT and converted into cysteine catalyzed by CTH. Glutamate, glycine, and cysteine are synthesized into GSH, which sustains the redox balance. Abbreviations: Ala, alanine; Glu, glutamate; Gln, glutamine; Aln, asparagine; Asp, aspartic acid; Gly, glycine; Ser, serine; Leu, leucine; Asn, asparagine; Cys, cysteine; a-KG, a-ketoglutarate; GSH, glutathione; PHGDH, phosphoglycerate dehydrogenase; PSAT1, phosphoserine aminotransferase; PSPH, phosphate ester hydrolysis; SHMT, serine hydroxymethyltransferase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GS: glutamine synthetase; GLS, glutaminase; GLUD, glutamate dehydrogenase; ASNS, asparagine synthetase; 3-PG, 3-phosphoglycerate; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; ADI, arginine deiminase; ASNS, asparagine synthetase; SLCs, membrane-bound solute carriers; CTH, cystathionine g-lyase.
Metabolism Genes Functional category of genes Role of HIF1 in metabolism Reference
Glycometabolism GLUT1
GLUT3		 Glucose uptake Increase [140]
[141]
HK2 Glucose phosphorylation Increase [142]
PGI
PFK1
ALDOA
TPI
GAPDH
PGK1
ENO1
PKM2
LDHA
PFKFB3		 Glycolysis Increase [143]
[143]
[143]
[143]
[143]
[143]
[143]
[143]
[143]
[144]
MCT4 Lactate excretion Increase [145]
PDK1
MXI1		 OXPHOS inhibition Increase PDK1 expression [143]
[143]
Lipid metabolism PPARg
FABPs
LRP1
VDLR		 Lipid uptake Increase [132]
[139]
[146]
[147]
SREBP-1
FASN
Lipin-1
AGPAT2		 Lipid synthesis Increase [148]
[148]
[134]
[135]
HIG2 Lipid accumulation Increase [149]
CPT1
PGC-1a
LCAD
MCAD		 FA b-oxidation Decrease [138]
[138]
[137]
[137]
Glutamine metabolism GLS1 Glutaminolysis Increase [150]
Tab.2  Hypoxia-inducible factor 1 (HIF1) downstream targets that regulate metabolism
Metabolism Genes Functional category of genes Role of c-Myc in metabolism Reference
Glycometabolism Glut1
Glut2
Glut4		 Glucose uptake Increase [169]
[170]
[170]
HK2 Glucose phosphorylation Increase [171]
PGI
PFK1
ALDOA
PGK1
ENO1
PKM2
LDHA		 Glycolysis Increase [172]
[170]
[170]
[170]
[170]
[171]
[171]
PDK1 OXPHOS inhibition Increase PDK1 expression [170]
Lipid metabolism FASN Lipid synthesis Increase [170]
Glutamine metabolism GLS1 Glutaminolysis Increase [171]
ASCT2 Glutamine uptake Increase [171]
Tab.3  c-Myc downstream targets that regulate metabolism
Metabolism Genes Functional category of genes Role of p53 in metabolism Reference
Glycometabolism GLUT4 Glucose uptake Decrease [43]
PGM1 Glycolysis Decrease [43]
TIGAR Decrease glycolysis and promote PPP Increase TIGAR expression [195]
SCO2, Acad11 OXPHOS Increase [195]
HK2 Glucose phosphorylation Decrease [43]
G6PD PPP Decrease [196]
Lipid metabolism Caveolin1 Lipid homeostasis and endocytosis Decrease [196]
SREBP1 Lipid synthesis Decrease [195]
DHR53, Lipin1, MCD Lipid accumulation Increase [196]
AMPK Promote FA b-Oxidation
and inhibit lipid synthesis		 Increase AMPK expression [196]
Glutamine metabolism GLS2 Glutaminolysis Increase [195]
Tab.4  p53 downstream targets that regulate metabolism
Proteins Modification Site Functional category Reference
HK2 Phosphorylation Thr473 Enhancing activity [210]
PFK1 Oxidation Ser529 Decreasing activity [211]
PFK2 Phosphorylation Ser466, Ser483 Enhancing activity [212]
PGAM1 Phosphorylation
Acetylation		 His11, Tyr26
Lys251, Lys253, Lys254		 Enhancing activity
Enhancing activity		 [213]
[214]
PKM2 Phosphorylation
Acetylation
Oxidation		 Ser37, Tyr105
Lys305, Lys433
Cys358		 Enhancing activity
Degradation
Decreasing activity		 [215,216]
[217]
[202]
PDP1 Phosphorylation
Acetylation		 Tyr381
Lys202		 Enhancing activity
Decreasing activity		 [218]
[218]
LDHA Phosphorylation
Acetylation		 Tyr10, Tyr 83
Lys5		 Enhancing activity
Degradation		 [200,219]
[201]
PDK1 Phosphorylation Tyr243, Tyr244 Enhancing activity [220]
PDHA1 Phosphorylation
Acetylation		 Ser293, Tyr301
Lys321		 Decreasing activity
Decreasing activity		 [221,222]
[218]
p53 Phosphorylation
Ubiquitylation
Acetylation		 Ser15
Lys237, Lys338
Lys		 Stabilization
Degradation
Stabilization		 [223]
[20]
[224]
HIF1a Ubiquitylation Lys709, Lys532 Degradation [225]
PPARg Phosphorylation
SUMOylation
Acetylation
Ubiquitylation		 Serine112
Lys63, Lys94, Lys98, Lys107
Lys268, Lys293
Lys184, Lys185		 Decreasing activity
Decreasing activity
Decreasing activity
Degradation		 [203]
[195]
[206]
[204,205]
SREBP1 Phosphorylation
Acetylation		 Thr402, Thr426
Lys324, Lys333		 Degradation
Stabilization		 [207]
[207,226]
GLS Phosphorylation
Phosphorylation
Acetylation		 Ser95
Ser314
Lys320		 Decreasing activity
Stabilization
Decreasing activity		 [208]
[209]
[227]
Tab.5  Post-translational modifications of proteins involved in metabolism
Fig.4  Vaccine-based therapies for breast cancer. The autologous cell-based vaccines uses the whole autologous tumor cells, which can submit almost all tumor antigens. Dendritic cell-based vaccines are finished following DC generation, TAA loading, or associated gene transfection. Peptide-based vaccines contain MHC I and MHC II epitopes and activate most CD4+ T cells and relatively few CD8+ T cells. DNA-based vaccines are usually delivered in the form of plasmids. Abbreviations: TAAs, tumor-associated antigens; APC, antigen-presenting cells.
Fig.5  Interplay between metabolism and immunity in cancer. On the one hand, abnormal metabolism in cancer cells creates a tumor microenvironment characterized by hypoxia, nutrient depletion, and acidic pH. This microenvironment can prevent T cells from increasing glycolysis and impair TCR signaling, thus suppressing their function. However, TAMs and Treg cells gain energy through fatty acid oxidation rather than glycolysis, whose characteristic helps them survive and exert their immunosuppressive effect. On the other hand, PD-1 and CTLA-4 can inhibit glycolysis in T cells, thus promoting cell death and inactivation. Furthermore, the expression levels of B7-H3 and PD-L1 promote glucose uptake, glucose utilization, and lactate production in breast cancer cells. Abbreviations: OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; TCR, T cell receptor; MHC, major histocompatibilty complex class; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4.
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