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.
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Li H, Zheng RS, Zhang SW, Zeng HM, Sun KX, Xia CF, Yang ZX, Chen WQ, He J. Incidence and mortality of female breast cancer in China, 2014. Chin J Oncol (Zhonghua Zhong LiuZaZhi) 2018; 40(3): 166–171 (in Chinese)
Stienstra R, Netea-Maier RT, Riksen NP, Joosten LAB, Netea MG. Specific and complex reprogramming of cellular metabolism in myeloid cells during innate immune responses. Cell Metab 2017; 26(1): 142–156
Kishton RJ, Sukumar M, Restifo NP. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab 2017; 26(1): 94–109
El Ansari R, McIntyre A, Craze ML, Ellis IO, Rakha EA, Green AR. Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations. Histopathology 2018; 72 (2): 183–190
Cappelletti V, Iorio E, Miodini P, Silvestri M, Dugo M, Daidone MG. Metabolic footprints and molecular subtypes in breast cancer. Dis Markers 2017; 2017: 7687851
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490(7418): 61–70
Holm K, Hegardt C, Staaf J, Vallon-Christersson J, Jönsson G, Olsson H, Borg A, Ringnér M. Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res 2010; 12(3): R36
Yersal O, Barutca S. Biological subtypes of breast cancer: prognostic and therapeutic implications. World J Clin Oncol 2014; 5(3): 412–424
Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200(3): 290–297
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009; 101(10): 736–750
Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, Kiezun A, Kryukov GV, Carter SL, Saksena G, Harris S, Shah RR, Resnick MA, Getz G, Gordenin DA. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 2013; 45(9): 970–976
Cheng YC, Rondón G, Anderlini P, Khouri IF, Champlin RE, Ueno NT. Paclitaxel and trastuzumab as maintenance therapy in patients with HER2-positive metastatic breast cancer who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation. J Cancer 2013; 4(8): 679–685
Duru N, Candas D, Jiang G, Li JJ. Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 2014; 140(1): 1–14
Malik F, Korkaya H, Clouthier SG, Wicha MS. Lin28 and HER2: two stem cell regulators conspire to drive aggressive breast cancer. Cell Cycle 2012; 11(15): 2780–2781
Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 2013; 73(12): 3489–3493
Russnes HG, Lingjærde OC, Børresen-Dale AL, Caldas C. Breast cancer molecular stratification: from intrinsic subtypes to integrative clusters. Am J Pathol 2017; 187(10): 2152–2162
Prat A, Cruz C, Hoadley KA, Díez O, Perou CM, Balmaña J. Molecular features of the basal-like breast cancer subtype based on BRCA1 mutation status. Breast Cancer Res Treat 2014; 147(1): 185–191
Kim SH, Choi SI, Won KY, Lim SJ. Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer. Pathol Res Pract 2016; 212(10): 904–910
Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science 2006; 312(5780): 1650–1653
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126(1): 107–120
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004; 64(11): 3892–3899
Xu J, Chen Y, Olopade OI. MYC and breast cancer. Genes Cancer 2010; 1(6): 629–640
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008; 105(48): 18782–18787
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458(7239): 762–765
Lim SO, Li CW, Xia W, Lee HH, Chang SS, Shen J, Hsu JL, Raftery D, Djukovic D, Gu H, Chang WC, Wang HL, Chen ML, Huo L, Chen CH, Wu Y, Sahin A, Hanash SM, Hortobagyi GN, Hung MC. EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Res 2016; 76(5): 1284–1296
Kanaan YM, Sampey BP, Beyene D, Esnakula AK, Naab TJ, Ricks-Santi LJ, Dasi S, Day A, Blackman KW, Frederick W, Copeland RL Sr, Gabrielson E, Dewitty RL Jr. Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteomics 2014; 11(6): 279–294
Kim S, Kim DH, Jung WH, Koo JS. Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer 2013; 20(3): 339–348
Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjøsne H, Giskeødegård GF, Bathen TF. Metabolic characterization of triple negative breast cancer. BMC Cancer 2014; 14(1): 941
McGuirk S, Gravel SP, Deblois G, Papadopoli DJ, Faubert B, Wegner A, Hiller K, Avizonis D, Akavia UD, Jones RG, Giguère V, St-Pierre J. PGC-1α supports glutamine metabolism in breast cancer. Cancer Metab 2013; 1(1): 22
Monaco ME. Fatty acid metabolism in breast cancer subtypes. Oncotarget 2017; 8(17): 29487–29500
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6(1): 1–6
Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, Eyob H, Kajimura S, Tward A, Krings G, Nomura DK, Goga A. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 2016; 22(4): 427–432
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab 2016; 23(1): 27–47
Benjamin DI, Cravatt BF, Nomura DK. Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metab 2012; 16(5): 565–577
Islam RA, Hossain S, Chowdhury EH. Potential therapeutic targets in energy metabolism pathways of breast cancer. Curr Cancer Drug Targets 2017; 17(8): 707–721
Jin L, Zhou Y. Crucial role of the pentose phosphate pathway in malignant tumors. Oncol Lett 2019; 17(5): 4213–4221
Wang Z, Dong C. Gluconeogenesis in cancer: function and regulation of PEPCK, FBPase, and G6Pase. Trends Cancer 2019; 5 (1): 30–45
Brovkovych V, Aldrich A, Li N, Atilla-Gokcumen GE, Frasor J. Removal of serum lipids and lipid-derived metabolites to investigate breast cancer cell biology. Proteomics 2019; 19(18): e1800370
Gomes L, Sorgine M, Passos CLA, Ferreira C, de Andrade IR, Silva JL, Atella GC, Mermelstein CS, Fialho E. Increase in fatty acids and flotillins upon resveratrol treatment of human breast cancer cells. Sci Rep 2019; 9(1): 13960
Gago-Dominguez M, Jiang X, Castelao JE. Lipid peroxidation, oxidative stress genes and dietary factors in breast cancer protection: a hypothesis. Breast Cancer Res 2007; 9(1): 201
Chen Z, Wang Y, Warden C, Chen S. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol 2015; 149: 118–127
Geck RC, Toker A. Nonessential amino acid metabolism in breast cancer. Adv Biol Regul 2016; 62: 11–17
Wu Z, Wu J, Zhao Q, Fu S, Jin J. Emerging roles of aerobic glycolysis in breast cancer. Clin Transl Oncol 2020; 22(5): 631–646
Macheda ML, Rogers S, Best JD. Molecularandcellularregulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005; 202(3): 654–662
Deng Y, Zou J, Deng T, Liu J. Clinicopathological and prognostic significance of GLUT1 in breast cancer: a meta-analysis. Medicine (Baltimore) 2018; 97(48): e12961
Liu H, Ertay A, Peng P, Li J, Liu D, Xiong H, Zou Y, Qiu H, Hancock D, Yuan X, Huang WC, Ewing RM, Downward J, Wang Y. SGLT1 is required for the survival of triple-negative breast cancer cells via potentiation of EGFR activity. Mol Oncol 2019; 13 (9): 1874–1886
Lai B, Xiao Y, Pu H, Cao Q, Jing H, Liu X. Overexpression of SGLT1 is correlated with tumor development and poor prognosis of ovarian carcinoma. Arch Gynecol Obstet 2012; 285(5): 1455–1461
Hanabata Y, Nakajima Y, Morita K, Kayamori K, Omura K. Coexpression of SGLT1 and EGFR is associated with tumor differentiation in oral squamous cell carcinoma. Odontology 2012; 100(2): 156–163
Casneuf VF, Fonteyne P, Van Damme N, Demetter P, Pauwels P, de Hemptinne B, De Vos M, Van de Wiele C, Peeters M. Expression of SGLT1, Bcl-2 and p53 in primary pancreatic cancer related to survival. Cancer Invest 2008; 26(8): 852–859
Brown RS, Goodman TM, Zasadny KR, Greenson JK, Wahl RL. Expression of hexokinase II and Glut-1 in untreated human breast cancer. Nucl Med Biol 2002; 29(4): 443–453
O’Neal J, Clem A, Reynolds L, Dougherty S, Imbert-Fernandez Y, Telang S, Chesney J, Clem BF. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer. Breast Cancer Res Treat 2016; 160(1): 29–40
Lin Y, Lv F, Liu F, Guo X, Fan Y, Gu F, Gu J, Fu L. High expression of pyruvate kinase M2 is associated with chemosensitivity to epirubicin and 5-fluorouracil in breast cancer. J Cancer 2015; 6(11): 1130–1139
Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, Chandel N, Laakso M, Muller WJ, Allen EL, Jha AK, Smolen GA, Clasquin MF, Robey B, Hay N. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013; 24(2): 213–228
Mishra D, Banerjee D. Lactate dehydrogenases as metabolic links between tumor and stroma in the tumor microenvironment. Cancers (Basel) 2019; 11(6): E750
Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL. Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins 2001; 43(2): 175–185
Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci 2014; 39(8): 347–354
Pu H, Zhang Q, Zhao C, Shi L, Wang Y, Wang J, Zhang M. Overexpression of G6PD is associated with high risks of recurrent metastasis and poor progression-free survival in primary breast carcinoma. World J Surg Oncol 2015; 13(1): 323
Yang X, Peng X, Huang J. Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation. Clin Transl Oncol 2018; 20(9): 1145–1152
Chen JQ, Russo J. Dysregulation ofglucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochim Biophys Acta 2012; 1826(2): 370–384
Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet 2014; 23(9): 2440–2446
Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab 2014; 99(10): E2046–E2050
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE, Downing JR. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015; 373 (24): 2336–2346
Fieuw A, Kumps C, Schramm A, Pattyn F, Menten B, Antonacci F, Sudmant P, Schulte JH, Van Roy N, Vergult S, Buckley PG, De Paepe A, Noguera R, Versteeg R, Stallings R, Eggert A, Vandesompele J, De Preter K, Speleman F. Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas. Int J Cancer 2012; 130(11): 2599–2606
Jiménez-Morales S, Pérez-Amado CJ, Langley E, Hidalgo-Miranda A. Overview of mitochondrial germline variants and mutations in human disease: focus on breast cancer. Int J Oncol 2018; 53(3): 923–936
Montal ED, Dewi R, Bhalla K, Ou L, Hwang BJ, Ropell AE, Gordon C, Liu WJ, DeBerardinis RJ, Sudderth J, Twaddel W, Boros LG, Shroyer KR, Duraisamy S, Drapkin R, Powers RS, Rohde JM, Boxer MB, Wong KK, Girnun GD. PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth. Mol Cell 2015; 60(4): 571–583
Chen J, Lee HJ, Wu X, Huo L, Kim SJ, Xu L, Wang Y, He J, Bollu LR, Gao G, Su F, Briggs J, Liu X, Melman T, Asara JM, Fidler IJ, Cantley LC, Locasale JW, Weihua Z. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. Cancer Res 2015; 75(3): 554–565
Cao Y. Obesity protects cancer from drugs targeting blood vessels. Cell Metab 2018; 27(6): 1163–1165
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029–1033
Baumann J, Sevinsky C, Conklin DS. Lipid biology of breast cancer. Biochim Biophys Acta 2013; 1831(10): 1509–1517
Zhao J, Zhi Z, Wang C, Xing H, Song G, Yu X, Zhu Y, Wang X, Zhang X, Di Y. Exogenous lipids promote the growth of breast cancer cells via CD36. Oncol Rep 2017; 38(4): 2105–2115
Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, Cheng L, Masterson TA, Liu X, Ratliff TL, Cheng JX. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 2014; 19(3): 393–406
Cao Y. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Invest 2019; 129(8): 3006–3017
Jung YY, Kim HM, Koo JS. Expression of lipid metabolism-related proteins in metastatic breast cancer. PLoS One 2015; 10(9): e0137204
Iwamoto H, Abe M, Yang Y, Cui D, Seki T, Nakamura M, Hosaka K, Lim S, Wu J, He X, Sun X, Lu Y, Zhou Q, Shi W, Torimura T, Nie G, Li Q, Cao Y. Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metab 2018; 28(1): 104–117.e5
Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol 2017; 24(9): 1161–1180
Min HY, Lee HY. Oncogene-driven metabolic alterations in cancer. Biomol Ther (Seoul) 2018; 26(1): 45–56
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012; 481(7381): 380–384
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104(49): 19345–19350
Szutowicz A, Kwiatkowski J, Angielski S. Lipogenetic and glycolytic enzyme activities in carcinoma and nonmalignant diseases of the human breast. Br J Cancer 1979; 39(6): 681–687
Lee JH, Jang H, Lee SM, Lee JE, Choi J, Kim TW, Cho EJ, Youn HD. ATP-citrate lyase regulates cellular senescence via an AMPK-and p53-dependent pathway. FEBS J 2015; 282(2): 361–371
Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes offatty acid and cholesterol biosynthesis. FEBS Lett 1987; 223(2): 217–222
Corominas-Faja B, Vellon L, Cuyàs E, Buxó M, Martin-Castillo B, Serra D, García J, Lupu R, Menendez JA. Clinical and therapeutic relevance of the metabolic oncogene fatty acid synthase in HER2+ breast cancer. Histol Histopathol 2017; 32(7): 687–698
Singh R, Cuervo AM. Lipophagy: connecting autophagy and lipid metabolism. Int J Cell Biol 2012; 2012: 282041
Yen MC, Kan JY, Hsieh CJ, Kuo PL, Hou MF, Hsu YL. Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance. Oncol Rep 2017; 37(6): 3253–3260
Orlando UD, Castillo AF, Medrano MAR, Solano AR, Maloberti PM, Podesta EJ. Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem Pharmacol 2019; 159: 52–63
Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA 1994; 91(14): 6379–6383
Freedman LS, Clifford C, Messina M. Analysis of dietary fat, calories, body weight, and the development ofmammary tumors in rats and mice: a review. Cancer Res 1990; 50(18): 5710–5719
Zimmerman AW, Veerkamp JH. New insights into the structure and function of fatty acid-binding proteins. Cell Mol Life Sci 2002; 59(7): 1096–1116
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, Yamada SD, Peter ME, Gwin K, Lengyel E. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17(11): 1498–1503
Li HY, Lv BB, Bi YH. FABP4 accelerates glioblastoma cell growth and metastasis through Wnt10b signalling. Eur Rev Med Pharmacol Sci 2018; 22(22): 7807–7818
Guaita-Esteruelas S, Bosquet A, Saavedra P, Gumà J, Girona J, Lam EW, Amillano K, Borràs J, Masana L. Exogenous FABP4 increases breast cancer cell proliferation and activates the expression of fatty acid transport proteins. Mol Carcinog 2017; 56(1): 208–217
Cheng F, Wang Z, Huang Y, Duan Y, Wang X. Investigation of salivary free amino acid profile for early diagnosis of breast cancer with ultra performance liquid chromatography-mass spectrometry. Clin Chim Acta 2015; 447: 23–31
Erickson JW, Cerione RA. Glutaminase: a hot spot for regulation of cancer cell metabolism? Oncotarget 2010; 1(8): 734–740
Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL, Eltayeb AE, Demas DM, Warri AM, Facey CO, Hilakivi-Clarke LA, Clarke R. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol Cancer 2014; 13(1): 239
Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T, Rabinowitz JD. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol 2013; 9(1): 712
Cha YJ, Kim ES, Koo JS. Amino acid transporters and glutamine metabolism in breast cancer. Int J Mol Sci 2018; 19(3): E907
van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O’Toole SA, Rasko JE, Holst J. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 2016; 35(24): 3201–3208
Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci 2012; 103(2): 382–389
Pollari S, Käkönen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 2011; 125(2): 421–430
Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011; 476(7360): 346–350
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012; 336(6084): 1040–1044
Kim SK, Jung WH, Koo JS. Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes. PLoS One 2014; 9(6): e101004
Labuschagne CF, van den Broek NJ, Mackay GM, Vousden KH, Maddocks OD. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep 2014; 7(4): 1248–1258
Schito L, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2016; 2(12): 758–770
Rey S, Schito L, Koritzinsky M, Wouters BG. Molecular targeting of hypoxia in radiotherapy. Adv Drug Deliv Rev 2017; 109: 45–62
Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ, van der Wall E. Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97(6): 1573–1581
Gruber G, Greiner RH, Hlushchuk R, Aebersold DM, Altermatt HJ, Berclaz G, Djonov V. Hypoxia-inducible factor 1 a in high-risk breast cancer: an independent prognostic parameter? Breast Cancer Res 2004; 6(3): R191–R198
Guo X, Lee S, Cao P. The inhibitive effect of sh-HIF1A-AS2 on the proliferation, invasion, and pathological damage of breast cancer via targeting miR-548c-3p through regulating HIF-1α/VEGF pathway in vitro and vivo. OncoTargets Ther2019; 12: 825–834
Wang Y, Zhang G, Han J. HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer. J Cell Biochem 2019; 120(6): 10513–10518
Zhang HS, Du GY, Zhang ZG, Zhou Z, Sun HL, Yu XY, Shi YT, Xiong DN, Li H, Huang YH. NRF2 facilitates breast cancer cell growth via HIF1-mediated metabolic reprogramming. Int J Biochem Cell Biol 2018; 95: 85–92
Ponente M, Campanini L, Cuttano R, Piunti A, Delledonne GA, Coltella N, Valsecchi R, Villa A, Cavallaro U, Pattini L, Doglioni C, Bernardi R. PML promotes metastasis of triple-negative breast cancer through transcriptional regulation of HIF1A target genes. JCI Insight 2017; 2(4): e87380
Sethuraman A, Brown M, Seagroves TN, Wu ZH, Pfeffer LM, Fan M. SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. Breast Cancer Res 2016; 18 (1): 81
Deb S, Johansson I, Byrne D, Nilsson C, kConFab Investigators, Constable L, Fjällskog ML, Dobrovic A, Hedenfalk I, Fox SB. Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer. Mod Pathol 2014; 27(9): 1223–1230
Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard PT Jr, Raman V, Zhen L, Mitzner WA, Sukumar S, Semenza GL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 2012; 31(14): 1757–1770
Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21(12): 3995–4004
Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 2000; 97(19): 10430–10435
Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia-related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117(12): 880–885
Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, Basso G, Leo G, Rosato A, Bicciato S, Cordenonsi M, Piccolo S. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 2012; 487(7407): 380–384
Koyasu S, Kobayashi M, Goto Y, Hiraoka M, Harada H. Regulatory mechanisms of hypoxia-inducible factor 1 activity: two decades of knowledge. Cancer Sci 2018; 109(3): 560–571
Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep 2015; 42(4): 841–851
Stubbs M, Griffiths JR. The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Adv Enzyme Regul 2010; 50(1): 44–55
Ebert BL, Firth JD, Ratcliffe PJ. Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem 1995; 270(49): 29083–29089
Tang Y, Zhu J, Huang D, Hu X, Cai Y, Song X, Song Z, Hong C, Feng Z, Kang F. Mandibular osteotomy-induced hypoxia enhances osteoclast activation and acid secretion by increasing glycolysis. J Cell Physiol 2019; 234(7): 11165–11175
Chiche J, Pommier S, Beneteau M, Mondragón L, Meynet O, Zunino B, Mouchotte A, Verhoeyen E, Guyot M, Pages G, Mounier N, Imbert V, Colosetti P, Goncalvès D, Marchetti S, Brière J, Carles M, Thieblemont C, Ricci JE. GAPDH enhances the aggressiveness and the vascularization of non-Hodgkin’s B lymphomas via NF-κB-dependent induction of HIF-1α. Leukemia 2015; 29(5): 1163–1176
Zhang T, Zhu X, Wu H, Jiang K, Zhao G, Shaukat A, Deng G, Qiu C. Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: combined administration of Polydatin and 2-Deoxy-d-glucose. J Cell Mol Med 2019; 23(5): 3711–3723
Hamaguchi T, Iizuka N, Tsunedomi R, Hamamoto Y, Miyamoto T, Iida M, Tokuhisa Y, Sakamoto K, Takashima M, Tamesa T, Oka M. Glycolysis module activated by hypoxia-inducible factor 1alpha is related to the aggressive phenotype of hepatocellular carcinoma. Int J Oncol 2008; 33(4): 725–731
Kraemer LD, Schulte PM. Prior PCB exposure suppresses hypoxia-induced up-regulation of glycolytic enzymes in Fundulus heteroclitus. Comp Biochem Physiol C Toxicol Pharmacol 2004; 139(1–3): 23–29
Cui XG, Han ZT, He SH, Wu XD, Chen TR, Shao CH, Chen DL, Su N, Chen YM, Wang T, Wang J, Song DW, Yan WJ, Yang XH, Liu T, Wei HF, Xiao J. HIF1/2a mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget 2017; 8 (15): 24840–24852
Sun Y, He W, Luo M, Zhou Y, Chang G, Ren W, Wu K, Li X, Shen J, Zhao X, Hu Y. SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism. Tumour Biol 2015; 36(6): 4133–4141
Li S, Oh YT, Yue P, Khuri FR, Sun SY. Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells. Oncogene 2016; 35(5): 642–650
Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8(3): 224–236
Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, Tokarska-Schlattner M, Aasum E, Bogdanova A, Perriard E, Perriard JC, Larsen T, Pedrazzini T, Krek W. Activation of a HIF1α-PPARγ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab 2009; 9(6): 512–524
Wang H, Airola MV, Reue K. How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862(10 Pt B): 1131–1145
Mylonis I, Sembongi H, Befani C, Liakos P, Siniossoglou S, Simos G. Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci 2012; 125(Pt 14): 3485–3493
Triantafyllou EA, Georgatsou E, Mylonis I, Simos G, Paraskeva E. Expression of AGPAT2, an enzyme involved in the glycerophospholipid/triacylglycerol biosynthesis pathway, is directly regulated by HIF-1 and promotes survival and etoposide resistance of cancer cells under hypoxia. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863(9): 1142–1152
Kucejova B, Sunny N E, Nguyen A D, Hallac R, Fu X, Pena-Llopis S, Mason RP, Deberardinis RJ, Xie XJ, Debose-Boyd R, Kodibagkar VD, Burgess SC, Brugarolas J. Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Oncogene 2011; 30(18): 2147–2160
Huang D, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL, Gao P, Zhang H. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 2014; 8(6): 1930–1942
Liu Y, Ma Z, Zhao C, Wang Y, Wu G, Xiao J, McClain CJ, Li X, Feng W. HIF-1α and HIF-2α are critically involved in hypoxia-induced lipid accumulation in hepatocytes through reducing PGC-1α-mediated fatty acid β-oxidation. Toxicol Lett 2014; 226(2): 117–123
Mylonis I, Simos G, Paraskeva E. Hypoxia-inducible factors and the regulation of lipid metabolism. Cells 2019; 8(3): E214
Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J Biol Chem 2001; 276(12): 9519–9525
Liu Q, Möller U, Flügel D, Kietzmann T. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood 2004; 104(13): 3993–4001
Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 2001; 276(46): 43407–43412
Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008; 8(9): 705–713
Jeon YK, Yoo DR, Jang YH, Jang SY, Nam MJ. Sulforaphane induces apoptosis in human hepatic cancer cells through inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase4, mediated by hypoxia inducible factor-1-dependent pathway. Biochim Biophys Acta 2011; 1814(10): 1340–1348
Ullah MS, Davies AJ, Halestrap AP. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1α-dependent mechanism. J Biol Chem 2006; 281 (14): 9030–9037
Castellano J, Aledo R, Sendra J, Costales P, Juan-Babot O, Badimon L, Llorente-Cortés V. Hypoxia stimulates low-density lipoprotein receptor-related protein-1 expression through hypoxia-inducible factor-1α in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2011; 31(6): 1411–1420
Perman JC, Boström P, Lindbom M, Lidberg U, StÅhlman M, Hägg D, Lindskog H, Scharin Täng M, Omerovic E, Mattsson Hultén L, Jeppsson A, Petursson P, Herlitz J, Olivecrona G, Strickland DK, Ekroos K, Olofsson SO, Borén J. The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. J Clin Invest 2011; 121 (7): 2625–2640
Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 2008; 68(4): 1003–1011
Gimm T, Wiese M, Teschemacher B, Deggerich A, Schödel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Höning S, Eckardt KU, Warnecke C. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J 2010; 24(11): 4443–4458
Xiang L, Mou J, Shao B, Wei Y, Liang H, Takano N, Semenza GL, Xie G. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis 2019; 10(2): 40
Deming SL, Nass SJ, Dickson RB, Trock BJ. C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br J Cancer 2000; 83(12): 1688–1695
Fallah Y, Brundage J, Allegakoen P, Shajahan-Haq AN. MYC-driven pathways in breast cancer subtypes. Biomolecules 2017; 7 (3): E53
Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 1997; 94(13): 6658–6663
Zhang Y, Zhang X, Wang X, Gan L, Yu G, Chen Y, Liu K, Li P, Pan J, Wang J, Qin S. Inhibition of LDH-A by lentivirus-mediated small interfering RNA suppresses intestinal-type gastric cancer tumorigenicity through the downregulation of Oct4. Cancer Lett 2012; 321(1): 45–54
Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 2004; 24(13): 5923–5936
Osthus RC, Shim H, Kim S, Li Q, Reddy R, Mukherjee M, Xu Y, Wonsey D, Lee LA, Dang CV. Deregulation ofglucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 2000; 275 (29): 21797–21800
Corn PG, Ricci MS, Scata KA, Arsham AM, Simon MC, Dicker DT, El-Deiry WS. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 2005; 4(11): 1285–1294
Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007; 12(2): 108–113
Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res 2007; 67(3): 854–855
Dang CV. The interplay between MYC and HIF in the Warburg effect. Ernst Schering Found Symp Proc 2007; (4): 35–53
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006; 3(3): 177–185
Lukey MJ, Wilson KF, Cerione RA. Therapeutic strategies impacting cancer cell glutamine metabolism. Future Med Chem 2013; 5(14): 1685–1700
Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ, Bellovin DI, Tran PT, Philbrick WM, Garcia-Ocana A, Casey SC, Li Y, Dang CV, Zare RN, Felsher DW. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci USA 2015; 112 (21): 6539–6544
Xiao D, Ren P, Su H, Yue M, Xiu R, Hu Y, Liu H, Qing G. Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2. Oncotarget 2015; 6(38): 40655–40666
Deng SJ, Chen HY, Zeng Z, Deng S, Zhu S, Ye Z, He C, Liu ML, Huang K, Zhong JX, Xu FY, Li Q, Liu Y, Wang C, Zhao G. Nutrient stress-dysregulated antisense lncRNA GLS-AS impairs GLS-mediated metabolism and represses pancreatic cancer progression. Cancer Res 2019; 79(7): 1398–1412
Craze ML, Cheung H, Jewa N, Coimbra NDM, Soria D, El-Ansari R, Aleskandarany MA, Wai Cheng K, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR. MYC regulation ofglutamine-proline regulatory axis is key in luminal B breast cancer. Br J Cancer 2018; 118(2): 258–265
Qie S, Chu C, Li W, Wang C, Sang N. ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation. J Cell Biochem 2014; 115(3): 498–509
Haikala HM, Marques E, Turunen M, Klefström J. Myc requires RhoA/SRF to reprogram glutamine metabolism. Small GTPases 2018; 9(3): 274–282
Sabnis HS, Somasagara RR, Bunting KD. Targeting MYC dependence by metabolic inhibitors in cancer. Genes (Basel) 2017; 8(4): E114
Soga T. Cancer metabolism: key players in metabolic reprogramming. Cancer Sci 2013; 104(3): 275–281
Liu R, Li Y, Tian L, Shi H, Wang J, Liang Y, Sun B, Wang S, Zhou M, Wu L, Nie J, Lin B, Tang S, Zhang Y, Wang G, Zhang C, Han J, Xu B, Liu L, Gong K, Zheng T. Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activating β-catenin/c-Myc signaling in human hepatocellular carcinoma. Cancer Lett 2019; 443: 34–46
Ritorto MS, Rhode H, Vogel A, Borlak J. Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC. Biol Chem 2016; 397(11): 1147–1162
Blevins MA, Towers CG, Patrick AN, Zhao R, Ford HL. The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 2015; 19(2): 213–225
Hua L, Fan L, Aichun W, Yongjin Z, Qingqing C, Xiaojian W. Inhibition of Six1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells. Tumour Biol 2014; 35(3): 1925–1931
Yu Y, Davicioni E, Triche TJ, Merlino G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res 2006; 66(4): 1982–1989
Jin H, Cui M, Kong J, Cui X, Lin Z, Wu Q, Liu S. Sineoculis homeobox homolog 1 protein is associated with breast cancer progression and survival outcome. Exp Mol Pathol 2014; 97(2): 247–252
Zhang Y, Wang S, Liu Z, Yang L, Liu J, Xiu M. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med 2019; 23(7): 4523–4533
Xie Y, Jin P, Sun X, Jiao T, Zhang Y, Li Y, Sun M. SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial-mesenchymal transition. Cell Biochem Funct 2018; 36(8): 413–419
Nishimura T, Tamaoki M, Komatsuzaki R, Oue N, Taniguchi H, Komatsu M, Aoyagi K, Minashi K, Chiwaki F, Shinohara H, Tachimori Y, Yasui W, Muto M, Yoshida T, Sakai Y, Sasaki H. SIX1 maintains tumor basal cells via transforming growth factor-β pathway and associates with poor prognosis in esophageal cancer. Cancer Sci 2017; 108(2): 216–225
Dumay A, Feugeas JP, Wittmer E, Lehmann-Che J, Bertheau P, Espié M, Plassa LF, Cottu P, Marty M, André F, Sotiriou C, Pusztai L, de Thé H. Distinct tumor protein p53 mutants in breast cancer subgroups. Int J Cancer 2013; 132(5): 1227–1231
Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 2018; 167(2): 417–423
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 2004; 64(7): 2627–2633
Watanabe M, Naraba H, Sakyo T, Kitagawa T. DNA damage-induced modulation of GLUT3 expression is mediated through p53-independent extracellular signal-regulated kinase signaling in HeLa cells. Mol Cancer Res 2010; 8(11): 1547–1557
Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res 2012; 72(2): 560–567
Mikawa T, Maruyama T, Okamoto K, Nakagama H, Lleonart ME, Tsusaka T, Hori K, Murakami I, Izumi T, Takaori-Kondo A, Yokode M, Peters G, Beach D, Kondoh H. Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2. J Cell Biol 2014; 204(5): 729–745
Boidot R, Végran F, Meulle A, Le Breton A, Dessy C, Sonveaux P, Lizard-Nacol S, Feron O. Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res 2012; 72(4): 939–948
Wang YB, Xu O, Zhang RJ, Shan CG. Study on the relationship between MCT-1 and p53 in laryngeal squamous cell carcinoma. J Clin Otorhinolaryngol Head Neck Surgery (Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi) 2017; 31(11): 825–829 (in Chinese)
Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, Yang X. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 2011; 13(3): 310–316
Geng J, Yuan X, Wei M, Wu J, Qin ZH. The diverse role of TIGAR in cellular homeostasis and cancer. Free Radic Res 2018; 52(11–12): 1240–1249
Ko YH, Domingo-Vidal M, Roche M, Lin Z, Whitaker-Menezes D, Seifert E, Capparelli C, Tuluc M, Birbe RC, Tassone P, Curry JM, Navarro-Sabaté À, Manzano A, Bartrons R, Caro J, Martinez-Outschoorn U. TP53-inducible glycolysis and apoptosis regulator (TIGAR) metabolically reprograms carcinoma and stromal cells in breast cancer. J Biol Chem 2016; 291(51): 26291–26303
Zhou JH, Zhang TT, Song DD, Xia YF, Qin ZH, Sheng R. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis. Sci Rep 2016; 6(1): 27096
Won KY, Lim SJ, Kim GY, Kim YW, Han SA, Song JY, Lee DK. Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer. Hum Pathol 2012; 43(2): 221–228
Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2013; 493 (7433): 542–546
Amelio I, Markert EK, Rufini A, Antonov AV, Sayan BS, Tucci P, Agostini M, Mineo TC, Levine AJ, Melino G. p73 regulates serine biosynthesis in cancer. Oncogene 2014; 33(42): 5039–5046
Liu J, Zhang C, Feng Z. Tumor suppressor p53 and its gain-of-function mutants in cancer. Acta Biochim Biophys Sin (Shanghai) 2014; 46(3): 170–179
Parrales A, Iwakuma T. p53 as a regulator of lipid metabolism in cancer. Int J Mol Sci 2016; 17(12): E2074
Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L. Cracking the estrogen receptor’s posttranslational code in breast tumors. Endocr Rev 2011; 32(5): 597–622
Vasudevan D, Hickok JR, Bovee RC, Pham V, Mantell LL, Bahroos N, Kanabar P, Cao XJ, Maienschein-Cline M, Garcia BA, Thomas DD. Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications. Cancer Res 2015; 75(24): 5299–5308
Matic S, Quaglino E, Arata L, Riccardo F, Pegoraro M, Vallino M, Cavallo F, Noris E. The rat ErbB2 tyrosine kinase receptor produced in plants is immunogenic in mice and confers protective immunity against ErbB2+ mammary cancer. Plant Biotechnol J 2016; 14(1): 153–159
Ji Y, Yang C, Tang Z, Yang Y, Tian Y, Yao H, Zhu X, Zhang Z, Ji J, Zheng X. Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation. Nat Commun 2017; 8(1): 15308
Zhao D, Zou SW, Liu Y, Zhou X, Mo Y, Wang P, Xu YH, Dong B, Xiong Y, Lei QY, Guan KL. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 2013; 23(4): 464–476
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS, Thomas CJ, Vander Heiden MG, Cantley LC. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011; 334(6060): 1278–1283
Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science 1996; 274(5295): 2100–2103
Floyd ZE, Stephens JM. Control of peroxisome proliferator-activated receptor g 2 stability and activity by SUMOylation. Obes Res 2004; 12(6): 921–928
Watanabe M, Takahashi H, Saeki Y, Ozaki T, Itoh S, Suzuki M, Mizushima W, Tanaka K, Hatakeyama S. The E3 ubiquitin ligase TRIM23 regulates adipocyte differentiation via stabilization of the adipogenic activator PPARg. eLife 2015; 4: e05615
Brunmeir R, Xu F. Functional regulation of PPARs through post-translational modifications. Int J Mol Sci 2018; 19(6): E1738
Xiaoping Z, Fajun Y. Regulation of SREBP-mediated gene expression. Sheng Wu Wu Li Hsueh Bao 2012; 28(4): 287–294
Ascenção CFR, Nagampalli RSK, Islam Z, Pinheiro MP, Menezes Dos Reis L, Pauletti BA, de Guzzi Cassago CA, Granato DC, Paes Leme AF, Dias SMG. N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration. Biochimie 2018; 154: 69–76
Han T, Zhan W, Gan M, Liu F, Yu B, Chin YE, Wang JB. Phosphorylation of glutaminase by PKCe is essential for its enzymatic activity and critically contributes to tumorigenesis. Cell Res 2018; 28(6): 655–669
Miyamoto S, Murphy AN, Brown JH. Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 2008; 15(3): 521–529
Yi W, Clark PM, Mason DE, Keenan MC, Hill C, Goddard WA 3rd, Peters EC, Driggers EM, Hsieh-Wilson LC. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science 2012; 337(6097): 975–980
Bertrand L, Alessi DR, Deprez J, Deak M, Viaene E, Rider MH, Hue L. Heart 6-phosphofructo-2-kinase activation by insulin results from Ser-466 and Ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase B. J Biol Chem 1999; 274(43): 30927–30933
Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Aleckovic M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, Chen J. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun 2013; 4(1): 1790
Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem 2012; 287(6): 3850–3858
Hitosugi T, Kang S, Vander Heiden MG, Chung TW, Elf S, Lythgoe K, Dong S, Lonial S, Wang X, Chen GZ, Xie J, Gu TL, Polakiewicz RD, Roesel JL, Boggon TJ, Khuri FR, Gilliland DG, Cantley LC, Kaufman J, Chen J. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci Signal 2009; 2(97): ra73
Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 2012; 14(12): 1295–1304
Lv L, Li D, Zhao D, Lin R, Chu Y, Zhang H, Zha Z, Liu Y, Li Z, Xu Y, Wang G, Huang Y, Xiong Y, Guan KL, Lei QY. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol Cell 2011; 42(6): 719–730
Fan J, Shan C, Kang HB, Elf S, Xie J, Tucker M, Gu TL, Aguiar M, Lonning S, Chen H, Mohammadi M, Britton LM, Garcia BA, Aleckovic M, Kang Y, Kaluz S, Devi N, Van Meir EG, Hitosugi T, Seo JH, Lonial S, Gaddh M, Arellano M, Khoury HJ, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 2014; 53(4): 534–548
Fan J, Hitosugi T, Chung TW, Xie J, Ge Q, Gu TL, Polakiewicz RD, Chen GZ, Boggon TJ, Lonial S, Khuri FR, Kang S, Chen J. Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD+ redox homeostasis in cancer cells. Mol Cell Biol 2011; 31(24): 4938–4950
Hitosugi T, Fan J, Chung TW, Lythgoe K, Wang X, Xie J, Ge Q, Gu TL, Polakiewicz RD, Roesel JL, Chen GZ, Boggon TJ, Lonial S, Fu H, Khuri FR, Kang S, Chen J. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell 2011; 44(6): 864–877
Fan J, Kang HB, Shan C, Elf S, Lin R, Xie J, Gu TL, Aguiar M, Lonning S, Chung TW, Arellano M, Khoury HJ, Shin DM, Khuri FR, Boggon TJ, Kang S, Chen J. Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 2014; 289(38): 26533–26541
Roche TE, Hiromasa Y. Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. Cell Mol Life Sci 2007; 64(7–8): 830–849
Yi G, He Z, Zhou X, Xian L, Yuan T, Jia X, Hong J, He L, Liu J. Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. Int J Oncol 2013; 43(5): 1503–1510
Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature 2000; 408(6810): 307–310
Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 2002; 111(5): 709–720
Giandomenico V, Simonsson M, Grönroos E, Ericsson J. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol Cell Biol 2003; 23 (7): 2587–2599
McDonald CJ, Acheff E, Kennedy R, Taylor L, Curthoys NP. Effect of lysine to alanine mutations on the phosphate activation and BPTES inhibition of glutaminase. Neurochem Int 2015; 88: 10–14
Engin A. Obesity-associated breast cancer: analysis of risk factors. Adv Exp Med Biol 2017; 960: 571–606
Haluska P, Menefee M, Plimack ER, Rosenberg J, Northfelt D, LaVallee T, Shi L, Yu XQ, Burke P, Huang J, Viner J, McDevitt J, LoRusso P. Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. Clin Cancer Res 2014; 20(18): 4747–4757
Liang J, Mills GB. AMPK: a contextual oncogene or tumor suppressor? Cancer Res 2013; 73(10): 2929–2935
Cao W, Li J, Hao Q, Vadgama JV, Wu Y. AMP-activated protein kinase: a potential therapeutic target for triple-negative breast cancer. Breast Cancer Res 2019; 21(1): 29
Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets 2017; 21(11): 1001–1016
Kageyama S, Ii H, Taniguchi K, Kubota S, Yoshida T, Isono T, Chano T, Yoshiya T, Ito K, Yoshiki T, Kawauchi A, Nakata S. Mechanisms of tumor growth inhibition by depletion of γ-glutamylcyclotransferase (GGCT): a novel molecular target for anticancer therapy. Int J Mol Sci 2018; 19(7): E2054
Ii H, Yoshiya T, Nakata S, Taniguchi K, Hidaka K, Tsuda S, Mochizuki M, Nishiuchi Y, Tsuda Y, Ito K, Kageyama S, Yoshiki T. A novel prodrug of a γ-glutamylcyclotransferase inhibitor suppresses cancer cell proliferation in vitro and inhibits tumor growth in a xenograft mouse model of prostate cancer. Chem-MedChem 2018; 13(2): 155–163
Curtin NJ, Hughes AN. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2001; 2(5): 298–306
Burnet FM. The concept ofimmunological surveillance. Prog Exp Tumor Res 1970; 13: 1–27
Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol 2014; 27: 16–25
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331(6024): 1565–1570
Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol 2013; 34(11): 556–563
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27(4): 450–461
Menzies AM, Long GV. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond. Eur J Cancer 2013; 49(15): 3229–3241
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192(2): 303–310
Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J. Cytotoxic T lymphocyte antigen 4 expression in human breast cancer: implications for prognosis. Cancer Immunol Immunother 2015; 64(7): 853–860
Ward FJ, Dahal LN, Wijesekera SK, Abdul-Jawad SK, Kaewarpai T, Xu H, Vickers MA, Barker RN. The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur J Immunol 2013; 43(5): 1274–1285
Laurent S, Queirolo P, Boero S, Salvi S, Piccioli P, Boccardo S, Minghelli S, Morabito A, Fontana V, Pietra G, Carrega P, Ferrari N, Tosetti F, Chang LJ, Mingari MC, Ferlazzo G, Poggi A, Pistillo MP. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-α production. J Transl Med 2013; 11(1): 108
Vonderheide RH, LoRusso PM, Khalil M, Gartner EM, Khaira D, Soulieres D, Dorazio P, Trosko JA, Rüter J, Mariani GL, Usari T, Domchek SM. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res 2010; 16(13): 3485–3494
McArthur HL, Diab A, Page DB, Yuan J, Solomon SB, Sacchini V, Comstock C, Durack JC, Maybody M, Sung J, Ginsberg A, Wong P, Barlas A, Dong Z, Zhao C, Blum B, Patil S, Neville D, Comen EA, Morris EA, Kotin A, Brogi E, Wen YH, Morrow M, Lacouture ME, Sharma P, Allison JP, Hudis CA, Wolchok JD, Norton L. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin Cancer Res 2016; 22(23): 5729–5737
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008; 224(1): 166–182
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27(1): 111–122
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027–1034
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24(2): 207–212
Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012; 366(26): 2517–2519
Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 2015; 6(7): 5449–5464
Chang LC, Chen TP, Kuo WK, Hua CC. The protein expression of PDL1 is highly correlated with those of eIF2a and ATF4 in lung cancer. Dis Markers 2018; 2018: 5068701
Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 2016; 27(3): 409–416
Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8(3): 239–245
Shi T, Ma Y, Yu L, Jiang J, Shen S, Hou Y, Wang T. Cancer immunotherapy: a focus on the regulation ofimmune checkpoints. Int J Mol Sci 2018; 19(5): E1389
Bedognetti D, Hendrickx W, Marincola FM, Miller LD. Prognostic and predictive immune gene signatures in breast cancer. Curr Opin Oncol 2015; 27(6): 433–444
Bedognetti D, Maccalli C, Bader SB, Marincola FM, Seliger B. Checkpoint inhibitors and their application in breast cancer. Breast Care (Basel) 2016; 11(2): 108–115
Planes-Laine G, Rochigneux P, Bertucci F, Chrétien AS, Viens P, Sabatier R, Gonçalves A. PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging. a literature review. Cancers (Basel) 2019; 11(7): E1033
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373(1): 23–34
Blackley EF, Loi S. Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast 2019; 48(Suppl 1): S44–S48
DeNardo DG, Coussens LM. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 2007; 9(4): 212
Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA 2012; 109(8): 2796–2801
Chin Y, Janseens J, Vandepitte J, Vandenbrande J, Opdebeek L, Raus J. Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer. Anticancer Res 1992; 12(5): 1463–1466
Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer 2016; 4(1): 59
Kurozumi S, Inoue K, Matsumoto H, Fujii T, Horiguchi J, Oyama T, Kurosumi M, Shirabe K. Prognostic utility of tumor-infiltrating lymphocytes in residual tumor after neoadjuvant chemotherapy with trastuzumab for HER2-positive breast cancer. Sci Rep 2019; 9 (1): 1583
Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, Syrjänen K. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 1992; 28(4–5): 859–864
Vikas P, Borcherding N, Zhang W. The clinical promise of immunotherapy in triple-negative breast cancer. Cancer Manag Res 2018; 10: 6823–6833
Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012; 11(3): 215–233
Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol 2016; 2(10): 1354–1360
Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, Goubar A. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol 2015; 26(8): 1698–1704
Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014; 32(27): 2959–2966
Zhang L, Wang XI, Ding J, Sun Q, Zhang S. The predictive and prognostic value of Foxp3+/CD25+ regulatory T cells and PD-L1 expression in triple negative breast cancer. Ann Diagn Pathol 2019; 40: 143–151
Luen SJ, Salgado R, Dieci MV, Vingiani A, Curigliano G, Gould RE, Castaneda C, D’Alfonso T, Sanchez J, Cheng E, Andreopoulou E, Castillo M, Adams S, Demaria S, Symmans WF, Michiels S, Loi S. Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy. Ann Oncol 2019; 30(2): 236–242
Criscitiello C. Tumor-associated antigens in breast cancer. Breast Care (Basel) 2012; 7(4): 262–266
Huber CH, Wölfel T. Immunotherapy of cancer: from vision to standard clinical practice. J Cancer Res Clin Oncol 2004; 130(7): 367–374
Dols A, Smith JW 2nd, Meijer SL, Fox BA, Hu HM, Walker E, Rosenheim S, Moudgil T, Doran T, Wood W, Seligman M, Alvord WG, Schoof D, Urba WJ. Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2-matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum Gene Ther 2003; 14(11): 1117–1123
Cibotti R, Kanellopoulos JM, Cabaniols JP, Halle-Panenko O, Kosmatopoulos K, Sercarz E, Kourilsky P. Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants. Proc Natl Acad Sci USA 1992; 89(1): 416–420
Shumway NM, Ibrahim N, Ponniah S, Peoples GE, Murray JL. Therapeutic breast cancer vaccines: a new strategy for early-stage disease. BioDrugs 2009; 23(5): 277–287
Park JW, Melisko ME, Esserman LJ, Jones LA, Wollan JB, Sims R. Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 over-expressing breast cancer. J Clin Oncol 2007; 25(24): 3680–3687
Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005; 5(4): 296–306
Ladjemi MZ, Jacot W, Chardès T, Pèlegrin A, Navarro-Teulon I. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother 2010; 59(9): 1295–1312
Cannon MJ, Block MS, Morehead LC, Knutson KL. The evolving clinical landscape for dendritic cell vaccines and cancer immunotherapy. Immunotherapy 2019; 11(2): 75–79
Saxena M, Balan S, Roudko V, Bhardwaj N. Towards superior dendritic-cell vaccines for cancer therapy. Nat Biomed Eng 2018; 2 (6): 341–346
Eagles ME, Nassiri F, Badhiwala JH, Suppiah S, Almenawer SA, Zadeh G, Aldape KD. Dendritic cell vaccines for high-grade gliomas. Ther Clin Risk Manag 2018; 14: 1299–1313
Sakai Y, Morrison BJ, Burke JD, Park JM, Terabe M, Janik JE, Forni G, Berzofsky JA, Morris JC. Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice. Cancer Res 2004; 64(21): 8022–8028
Peoples GE, Goedegebuure PS, Smith R, Linehan DC, Yoshino I, Eberlein TJ. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 1995; 92(2): 432–436
Al-Awadhi A, Lee Murray J, Ibrahim NK. Developing anti-HER2 vaccines: breast cancer experience. Int J Cancer 2018; 143(9): 2126–2132
Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E, Pedicano JE, Gehan E, Peck RA, Arlen P, Tsang KY, Schlom J. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anticarcinoembryonic antigen immune responses. J Clin Oncol 2000; 18(23): 3964–3973
Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Seipp CA, Einhorn JH, Roberts B, White DE. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J Natl Cancer Inst 1998; 90(24): 1894–1900
Yang B, Jeang J, Yang A, Wu TC, Hung CF. DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother 2014; 10(11): 3153–3164
Norell H, Poschke I, Charo J, Wei WZ, Erskine C, Piechocki MP, Knutson KL, Bergh J, Lidbrink E, Kiessling R. Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med 2010; 8(1): 53
Chae YC, Kim JH. Cancer stem cell metabolism: target for cancer therapy. BMB Rep 2018; 51(7): 319–326
Louhichi T, Ziadi S, Saad H, Dhiab MB, Mestiri S, Trimeche M. Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer. Breast Cancer 2018; 25 (6): 698–705
Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, Sugihara E, Onishi N, Yamamoto T, Yanagawa H, Suematsu M, Saya H. Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res 2012; 72(6): 1438–1448
Liu PP, Liao J, Tang ZJ, Wu WJ, Yang J, Zeng ZL, Hu Y, Wang P, Ju HQ, Xu RH, Huang P. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ 2014; 21(1): 124–135
Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014; 514(7524): 628–632
Gao C, Shen Y, Jin F, Miao Y, Qiu X. Cancer stem cells in small cell lung cancer cell line H446: higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS One 2016; 11(5): e0154576
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sanchez V, Sanders ME, Lee T, Gomez H, Lluch A, Perez-Fidalgo J A, Wolf MM, Andrejeva G, Rathmell J C, Fesik S W, Arteaga CL. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab 2017; 26(4): 633–647.e7
Tirinato L, Liberale C, Di Franco S, Candeloro P, Benfante A, La Rocca R, Potze L, Marotta R, Ruffilli R, Rajamanickam VP, Malerba M, De Angelis F, Falqui A, Carbone E, Todaro M, Medema JP, Stassi G, Di Fabrizio E. Lipid droplets: a new player in colorectal cancer stem cells unveiled by spectroscopic imaging. Stem Cells 2015; 33(1): 35–44
Wang T, Fahrmann J F, Lee H, Li Y J, Tripathi S C, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, Somlo G, Jandial R, Ann D, Hanash S, Jove R, Yu H. JAK/STAT3-regulated fatty acid beta-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 2018; 27(1): 136–150.e5
Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-oncol 2010; 12(11): 1113–1125
Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S, Udupi GM, Gallagher WM, Wegner C, West BL, Wang-Gillam A, Goedegebuure P, Linehan DC, DeNardo DG. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73(3): 1128–1141
Bottino C, Castriconi R, Moretta L, Moretta A. Cellular ligands of activating NK receptors. Trends Immunol 2005; 26(4): 221–226
Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, Mortini P, Ferrone S, Doglioni C, Marincola FM, Galli R, Parmiani G, Maccalli C. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res 2010; 16(3): 800–813
Silver DJ, Sinyuk M, Vogelbaum MA, Ahluwalia MS, Lathia JD. The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities. Neuro-oncol 2016; 18(2): 153–159
Almozyan S, Colak D, Mansour F, Alaiya A, Al-Harazi O, Qattan A, Al-Mohanna F, Al-Alwan M, Ghebeh H. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer 2017; 141 (7): 1402–1412
Biswas SK. Metabolic reprogramming of immune cells in cancer progression. Immunity 2015; 43(3): 435–449
Zhu L, Zhao Q, Yang T, Ding W, Zhao Y. Cellular metabolism and macrophage functional polarization. Int Rev Immunol 2015; 34(1): 82–100
Ho PC, Liu PS. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. J Immunother Cancer 2016; 4(1): 4
Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 2013; 24(6): 695–709
Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 2003; 163(4): 1233–1243
Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003; 112(5): 645–657
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513(7519): 559–563
Cassim S, Pouyssegur J. Tumor microenvironment: a metabolic player that shapes the immune response. Int J Mol Sci 2019; 21(1): E157
Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai S W, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 2019; 178(1): 176–189.e15
Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153(6): 1239–1251
Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G, Yurchenko E, Raissi TC, van der Windt GJ, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 2015; 42(1): 41–54
Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186(6): 3299–3303
Siska PJ, Rathmell JC. T cell metabolic fitness in antitumor immunity. Trends Immunol 2015; 36(4): 257–264
Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 2014; 211(5): 781–790
Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16(6): 769–777
Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015; 6(1): 6692
Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162(6): 1229–1241
Saleh R, Taha RZ, Sasidharan Nair V, Alajez NM, Elkord E. PD-L1 blockade by atezolizumab downregulates signaling pathways associated with tumor growth, metastasis, and hypoxia in human triple negative breast cancer. Cancers (Basel) 2019; 11(8): E1050
Lim S, Liu H, Madeira da Silva L, Arora R, Liu Z, Phillips JB, Schmitt DC, Vu T, McClellan S, Lin Y, Lin W, Piazza GA, Fodstad O, Tan M. Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1α. Cancer Res 2016; 76(8): 2231–2242
Franchina DG, He F, Brenner D. Survival of the fittest: cancer challenges T cell metabolism. Cancer Lett 2018; 412: 216–223
Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 2009; 8(1): 88–96
Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 2010; 123(1): 271–279
Zhou X, Chen J, Yi G, Deng M, Liu H, Liang M, Shi B, Fu X, Chen Y, Chen L, He Z, Wang J, Liu J. Metformin suppresses hypoxia-induced stabilization of HIF-1 a through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 2016; 7(1): 873–884
Xue J, Li L, Li N, Li F, Qin X, Li T, Liu M. Metformin suppresses cancer cell growth in endometrial carcinoma by inhibiting PD-L1. Eur J Pharmacol 2019; 859: 172541
Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, Li CW, Kim T, Chang SS, Lee HH, Hsu JL, Wang HL, Kuo CW, Chang WC, Hadad S, Purdie CA, McCoy AM, Cai S, Tu Y, Litton JK, Mittendorf EA, Moulder SL, Symmans WF, Thompson AM, Piwnica-Worms H, Chen CH, Khoo KH, Hung MC. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Mol Cell 2018; 71(4): 606–620.e7
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Deyu Zhang, Xiaojie Xu, and Qinong Ye declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.
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Zhang, D., Xu, X. & Ye, Q. Metabolism and immunity in breast cancer. Front. Med. 15, 178–207 (2021). https://doi.org/10.1007/s11684-020-0793-6
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DOI: https://doi.org/10.1007/s11684-020-0793-6