Amino acid metabolism in breast cancer: pathogenic drivers and therapeutic opportunities

Abstract

Amino acid metabolism plays a critical role in the progression and development of breast cancer. Cancer cells, including those in breast cancer, reprogram amino acid metabolism to meet the demands of rapid proliferation, survival, and immune evasion. This includes alterations in the uptake and utilization of amino acids, such as glutamine, serine, glycine, and arginine, which provide essential building blocks for biosynthesis, energy production, and redox homeostasis. Notably, the metabolic phenotypes of breast cancer cells vary across molecular subtypes and disease stages, emphasizing the need for patient stratification and personalized therapeutic strategies. Advances in multi- level diagnostics, including phenotyping and predictive tools, such as AI-based analysis and body fluid profiling, have highlighted the potential for tailoring treatments to individual metabolic profiles. Enzymes, such as glutaminase and serine hydroxymethyltransferase, often upregulated in breast cancer, represent promising therapeutic targets. Understanding the interplay between amino acid metabolism and breast cancer biology, alongside the integration of personalized medicine approaches, can uncover novel insights into tumor progression and guide the development of precision therapies. This review explores the metabolic pathways of amino acids in breast cancer, with a focus on their implications for personalized treatment strategies.

Keywords

amino acid metabolism / breast cancer / metabolic reprogramming / cancer therapy / personalized medicine

References

[1] Acosta JN, Falcone GJ, Rajpurkar P et al. Multimodal biomedical AI. Nat Med 2022;28:1773–1784.

[2] Afsharzadeh M, Varshosaz J, Mirian M et al. Targeted delivery of liposomal Ribociclib to SLC7A5 transporters in breast cancer cells. Invest New Drugs 2024;42:89–105.

[3] Alba-Bernal A, Godoy-Ortiz A, Dominguez-Recio ME et al. Increased blood draws for ultrasensitive ctDNA and CTCs detection in early breast cancer patients. NPJ Breast Cancer 2024;10:36.

[4] Alcin G, Tatar G, Menengic Koc MS et al. Complex fibroadenoma mimicking breast cancer on ⁶⁸Ga-FAPI-04 and ¹⁸F-FDG PET/CT. Clin Nucl Med 2023;48:e121–e123.

[5] Alfarsi LH, El Ansari R, Craze ML et al. SLC1A5 co-expression with TALDO1 associates with endocrine therapy failure in estrogen receptor-positive breast cancer. Breast Cancer Res Treat 2021;189:317–331.

[6] Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 2016;16:619–634.

[7] Babu E, Bhutia YD, Ramachandran S et al. Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer. Biochem J 2015;469:17–23.

[8] Bacci M, Lorito N, Ippolito L et al. Reprogramming of amino acid transporters to support aspartate and glutamate dependency sustains endocrine resistance in breast cancer. Cell Rep 2019;28:104–118.e8.

[9] Baek S, Choi CM, Ahn SH et al. Exploratory clinical trial of (4S)-4-(3-[18F]fluoropropyl)-L-glutamate for imaging xC-transporter using positron emission tomography in patients with non-small cell lung or breast cancer. Clin Cancer Res 2012;18:5427–5437.

[10] Barnabas GD, Lee JS, Shami T et al. Serine biosynthesis is a metabolic vulnerability in IDH2-driven breast cancer progression. Cancer Res 2021;81:1443–1456.

[11] Bernhardt S, Bayerlova M, Vetter M et al. Proteomic profiling of breast cancer metabolism identifies SHMT2 and ASCT2 as prognostic factors. Breast Cancer Res 2017;19:112.

[12] Bray F, Laversanne M, Sung H et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229–263.

[13] Broer A, Fairweather S, Broer S. Disruption of amino acid homeostasis by novel ASCT2 inhibitors involves multiple targets. Front Pharmacol 2018;9:785.

[14] Brown KA. Metabolic pathways in obesity-related breast cancer. Nat Rev Endocrinol 2021;17:350–363.

[15] Brumano LP, da Silva FVS, Costa-Silva TA et al. Development of L-Asparaginase Biobetters: current research status and review of the desirable quality profiles. Front Bioeng Biotechnol 2018;6:212.

[16] Chen Z, Wang Y, Warden C et al. 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.

[17] Chen L, Cui H, Fang J et al. Glutamine deprivation plus BPTES alters etoposide-and cisplatin-induced apoptosis in triple negative breast cancer cells. Oncotarget 2016;7:54691–54701.

[18] Chen CL, Hsu SC, Ann DK et al. Arginine signaling and cancer metabolism. Cancers (Basel) 2021;13:3541.

[19] Cheng CT, Qi Y, Wang YC et al. Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Commun Biol 2018;1:178.

[20] Chi R, Yao C, Chen S et al. Elevated BCAA suppresses the development and metastasis of breast cancer. Front Oncol 2022;12:887257.

[21] Cluntun AA, Lukey MJ, Cerione RA et al. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 2017;3:169–180.

[22] Coloff JL, Murphy JP, Braun CR et al. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metab 2016;23:867–880.

[23] Colombero C, Remy D, Antoine-Bally S et al. mTOR repression in response to amino acid starvation promotes ECM degradation through MT1-MMP endocytosis arrest. Adv Sci (Weinh) 2021;8:e2101614.

[24] Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (^c)(^-): cystine supplier and beyond. Amino Acids 2012;42:231–246.

[25] Cormerais Y, Massard PA, Vucetic M et al. The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem 2018;293:2877–2887.

[26] D’Amato NC, Rogers TJ, Gordon MA et al. A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer. Cancer Res 2015;75:4651–4664.

[27] Daidone F, Florio R, Rinaldo S et al. In silico and in vitro validation of serine hydroxymethyltransferase as a chemotherapeutic target of the antifolate drug pemetrexed. Eur J Med Chem 2011;46:1616–1621.

[28] Danzi F, Pacchiana R, Mafficini A et al. To metabolomics and beyond: a technological portfolio to investigate cancer metabolism. Signal Transduct Target Ther 2023;8:137.

[29] de Groot S, Lugtenberg RT, Cohen D et al. Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun 2020;11:3083.

[30] Deng L, Yao P, Li L et al. p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival. Nat Commun 2020;11:1755.

[31] Dias MM, Adamoski D, Dos Reis LM et al. GLS2 is protumorigenic in breast cancers. Oncogene 2020;39:690–702.

[32] Doglioni G, Fernandez-Garcia J, Igelmann S et al. Aspartate signalling drives lung metastasis via alternative translation. Nature 2025;638:244–250.

[33] Dong J, Xiao D, Zhao Z et al. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism. Oncogenesis 2017;6:e356.

[34] El Ansari R, Craze ML, Miligy I et al. 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. Breast Cancer Res 2018;20:21.

[35] El-Botty R, Morriset L, Montaudon E et al. Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers. Nat Commun 2023;14:4221.

[36] Fan Y, Zhou X, Xia TS et al. Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer. Oncotarget 2016;7:9925–9938.

[37] Feng S, Aplin C, Nguyen TT et al. Filament formation drives catalysis by glutaminase enzymes important in cancer progression. Nat Commun 2024;15:1971.

[38] Gallagher FA, Woitek R, McLean MA et al. Imaging breast cancer using hyperpolarized carbon-13 MRI. Proc Natl Acad Sci U S A 2020;117:2092–2098.

[39] Gao P, Tchernyshyov I, Chang TC et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009;458:762–765.

[40] Garcia-Bermudez J, Baudrier L, La K et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat Cell Biol 2018;20:775–781.

[41] Gauthier-Coles G, Broer A, McLeod MD et al. Identification and characterization of a novel SNAT2 (SLC38A2) inhibitor reveals synergy with glucose transport inhibition in cancer cells. Front Pharmacol 2022;13:963066.

[42] Geeraerts SL, Kampen KR, Rinaldi G et al. Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis-addicted breast tumor growth. Mol Cancer Ther 2021;20:50–63.

[43] Golubnitschaja O, Kapinova A, Sargheini N et al. Miniencyclopedia of mitochondria-relevant nutraceuticals protecting health in primary and secondary care-clinically relevant 3PM innovation. EPMA J 2024;15:163–205.

[44] Gorgoglione R, Impedovo V, Riley CL et al. Glutamine-derived aspartate biosynthesis in cancer cells: role of mitochondrial transporters and new therapeutic perspectives. Cancers (Basel) 2022;14:245.

[45] Gross MI, Demo SD, Dennison JB et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 2014;13:890–901.

[46] Guney Eskiler G, Bilir C. The efficacy of indoximod upon stimulation with pro-inflammatory cytokines in triplenegative breast cancer cells. Immunopharmacol Immunotoxicol 2021;43:554–561.

[47] Hickok JR, Vasudevan D, Antholine WE et al. Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem 2013;288:16004–16015.

[48] Hong R, Zhou Y, Tian X et al. Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1(hi)breast cancer via enhancing immune cells activity. Int Immunopharmacol 2018;54:118–124.

[49] Hong R, Zhang W, Xia X et al. Preventing BRCA1/ZBRK1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation. Mol Oncol 2019;13:959–977.

[50] Hsu WJ, Chiang MC, Chao YC et al. Arginine methylation of DDX3 by PRMT1 mediates mitochondrial homeostasis to promote breast cancer metastasis. Cancer Res 2024;84:3023–3043.

[51] Huang R, Wang H, Hong J et al. Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer. Front Immunol 2023;14:1251643.

[52] Huang L, Li G, Zhang Y et al. Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells. J Adv Res 2024;24:476.

[53] Issaq SH, Mendoza A, Fox SD et al. Glutamine synthetase is necessary for sarcoma adaptation to glutamine deprivation and tumor growth. Oncogenesis 2019;8:20.

[54] Jacquemier J, Bertucci F, Finetti P et al. High expression of indoleamine 2, 3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. Int J Cancer 2012;130:96–104.

[55] Janssen FW, Lak NSM, Janda CY et al. A comprehensive overview of liquid biopsy applications in pediatric solid tumors. NPJ Precis Oncol 2024;8:172.

[56] Jeon YJ, Khelifa S, Ratnikov B et al. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 2015;27:354–369.

[57] Jeong SM, Xiao C, Finley LW et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013;23:450–463.

[58] Jhaveri K, Modi S. Ganetespib: research and clinical development. Onco Targets Ther 2015;8:1849–1858.

[59] Jiao Z, Pan Y, Chen F. The metabolic landscape of breast cancer and its therapeutic implications. Mol Diagn Ther 2023;27:349–369.

[60] Jin J, Byun JK, Choi YK et al. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp Mol Med 2023;55:706–715.

[61] Jung KH, LoRusso P, Burris H et al. Phase I study of the Indoleamine 2, 3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) administered with PD-L1 Inhibitor (Atezolizumab) in advanced solid tumors. Clin Cancer Res 2019;25:3220–3228.

[62] Jung MK, Okekunle AP, Lee JE et al. Role of branched-chain amino acid metabolism in tumor development and progression. J Cancer Prev 2021;26:237–243.

[63] Karunakaran S, Ramachandran S, Coothankandaswamy V et al. SLC6A14 (ATB^0,+) protein, a highly concentrative and broad specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer. J Biol Chem 2011;286:31830–31838.

[64] Keshet R, Erez A. Arginine and the metabolic regulation of nitric oxide synthesis in cancer. Dis Model Mech 2018;11:dmm033332.

[65] Kikuchi Y, Hiroshima Y, Matsuo K et al. A randomized clinical trial of preoperative administration of branched-chain amino acids to prevent postoperative ascites in patients with liver resection for hepatocellular carcinoma. Ann Surg Oncol 2016;23:3727–3735.

[66] Kim GW, Lee DH, Jeon YH et al. Glutamine synthetase as a therapeutic target for cancer treatment. Int J Mol Sci 2021;22:1701.

[67] Knott SRV, Wagenblast E, Khan S et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 2018;554:378–381.

[68] Koppula P, Zhang Y, Zhuang L et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (Lond) 2018;38:12.

[69] Kottakis F, Nicolay BN, Roumane A et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 2016;539:390–395.

[70] Lee G, Wong C, Cho A et al. E-cadherin induces serine synthesis to support progression and metastasis of breast cancer. Cancer Res 2024;84:2820–2835.

[71] Lei M, Zhang YL, Huang FY et al. Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells. Sci Rep 2023;13:21916.

[72] Levina V, Su Y, Gorelik E. Immunological and nonimmunological effects of indoleamine 2, 3-dioxygenase on breast tumor growth and spontaneous metastasis formation. Clin Dev Immunol 2012;2012:173029.

[73] Li L, Di X, Wu M et al. Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy. Nanomedicine 2017;13:987–998.

[74] Li Y, Wang W, Wu X et al. SLC7A5 serves as a prognostic factor of breast cancer and promotes cell proliferation through activating AKT/mTORC1 signaling pathway. Ann Transl Med 2021;9:892.

[75] Liang Z, Cho HT, Williams L et al. Potential biomarker of L-type amino acid transporter 1 in breast cancer progression. Nucl Med Mol Imaging 2011;45:93–102.

[76] Lieu EL, Nguyen T, Rhyne S et al. Amino acids in cancer. Exp Mol Med 2020;52:15–30.

[77] Ling ZN, Jiang YF, Ru JN et al. Amino acid metabolism in health and disease. Signal Transduct Target Ther 2023;8:345.

[78] Liu X, Ren B, Ren J et al. The significant role of amino acid metabolic reprogramming in cancer. Cell Commun Signal 2024a;22:380.

[79] Liu Y, Chen S, Wan X et al. Tryptophan 2, 3-dioxygenasepositive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction. Cancer Commun (Lond) 2024b;44:1261–1286.

[80] Locasale JW, Cantley LC. Genetic selection for enhanced serine metabolism in cancer development. Cell Cycle 2011;10:3812–3813.

[81] Loibl S, André F, Bachelot T et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2024;35:159–182.

[82] Long GV, Dummer R, Hamid O et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol 2019;20:1083–1097.

[83] Lukey MJ, Cluntun AA, Katt WP et al. Liver-Type Glutaminase GLS2 Is a druggable metabolic node in luminal-subtype breast cancer. Cell Rep 2019;29:76–88.e7.

[84] Luo W, Zou Z, Nie Y et al. ASS1 inhibits triple-negative breast cancer by regulating PHGDH stability and de novo serine synthesis. Cell Death Dis 2024;15:319.

[85] Mariotti V, Han H, Ismail-Khan R et al. Effect of taxane chemotherapy with or without indoximod in metastatic breast cancer: a randomized clinical trial. JAMA Oncol 2021;7:61–69.

[86] Maris M, Salles G, Kim WS et al. ASCT2-targeting antibody-drug conjugate MEDI7247 in adult patients with relapsed/refractory hematological malignancies: a first-in-human, Phase 1 study. Target Oncol 2024;19:321–332.

[87] Masisi BK, El Ansari R, Alfarsi L et al. The biological and clinical significance of glutaminase in luminal breast cancer. Cancers (Basel) 2021;13:3963.

[88] Mathew M, Sivaprakasam S, Dharmalingam-Nandagopal G et al. Induction of oxidative stress and ferroptosis in triple-negative breast cancer cells by niclosamide via blockade of the function and expression of SLC38A5 and SLC7A11. Antioxidants (Basel) 2024;13:291.

[89] Meireson A, Devos M, Brochez L. IDO expression in cancer: different compartment, different functionality? Front Immunol 2020;11:531491.

[90] Metcalf S, Petri BJ, Kruer T et al. Serine synthesis influences tamoxifen response in ER+ human breast carcinoma. Endocr Relat Cancer 2021;28:27–37.

[91] Miller IJ, Peters SR, Overmyer KA et al. Real-time health monitoring through urine metabolomics. NPJ Digit Med 2019;2:109.

[92] Mitchell TC, Hamid O, Smith DC et al. Epacadostat Plus Pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label Phase I/II Trial (ECHO-202/KEYNOTE-037). J Clin Oncol 2018;36:3223–3230.

[93] Morotti M, Bridges E, Valli A et al. Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer. Proc Natl Acad Sci U S A 2019;116:12452–12461.

[94] Morotti M, Zois CE, El-Ansari R et al. Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer. Br J Cancer 2021;124:494–505.

[95] Mullarky E, Lucki NC, Beheshti Zavareh R et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc Natl Acad Sci U S A 2016;113:1778–1783.

[96] Nalecz KA. Amino Acid Transporter SLC6A14 (ATB^0,+) – A target in combined anti-cancer therapy. Front Cell Dev Biol 2020;8:594464.

[97] Nath P, Alfarsi LH, El-Ansari R et al. The amino acid transporter SLC7A11 expression in breast cancer. Cancer Biol Ther 2024;25:2291855.

[98] Nayak-Kapoor A, Hao Z, Sadek R et al. Phase Ia study of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. J ImmunoTher Cancer 2018;6:61.

[99] Novikov O, Wang Z, Stanford EA et al. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER–PR–/Her2^-human breast cancer cells. Mol Pharmacol 2016;90:674–688.

[100] Oda K, Hosoda N, Endo H et al. L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci 2010;101:173–179.

[101] Onesti CE, Boemer F, Josse C et al. Tryptophan catabolism increases in breast cancer patients compared to healthy controls without affecting the cancer outcome or response to chemotherapy. J Transl Med 2019;17:239.

[102] Ong ZY, Chen S, Nabavi E et al. Multibranched gold nanoparticles with intrinsic LAT-1 targeting capabilities for selective photothermal therapy of breast cancer. ACS Appl Mater Interfaces 2017;9:39259–39270.

[103] Pacold ME, Brimacombe KR, Chan SH et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol 2016;12:452–458.

[104] Parida PK, Marquez-Palencia M, Nair V et al. Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness. Cell Metab 2022;34:90–105.e7.

[105] Pesta M, Mrazova B, Kapalla M et al. Mitochondria-based holistic 3PM approach as the ‘game-changer’ for individualised rehabilitation-the proof-of-principle model by treated breast cancer survivors. EPMA J 2024;15:559–571.

[106] Platten M, Nollen EAA, Rohrig UF et al. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov 2019;18:379–401.

[107] Pollari S, Kakonen SM, Edgren H et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 2011;125:421–430.

[108] Possemato R, Marks KM, Shaul YD et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011;476:346–350.

[109] Qie S, Chu C, Li W et al. ErbB2 activation upregulates glutaminase 1 expression which promotes breast cancer cell proliferation. J Cell Biochem 2014;115:498–509.

[110] Qiu F, Chen YR, Liu X et al. Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells. Sci Signal 2014;7:ra31.

[111] Quek LE, van Geldermalsen M, Guan YF et al. Glutamine addiction promotes glucose oxidation in triple-negative breast cancer. Oncogene 2022;41:4066–4078.

[112] Rabinovich S, Adler L, Yizhak K et al. Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis. Nature 2015;527:379–383.

[113] Ramachandran S, S RS, Sharma M et al. Expression and function of SLC38A5, an amino acid-coupled Na⁺/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis. Biochem J 2021;478:3957–3976.

[114] Reis LMD, Adamoski D, Ornitz Oliveira Souza R et al. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. J Biol Chem 2019;294:9342–9357.

[115] Reynolds MR, Lane AN, Robertson B et al. Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 2014;33:556–566.

[116] Robinson MM, McBryant SJ, Tsukamoto T et al. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem J 2007;406:407–414.

[117] Roci I, Watrous JD, Lagerborg KA et al. Mapping metabolic events in the cancer cell cycle reveals arginine catabolism in the committed SG₂M Phase. Cell Rep 2019;26:1691–1700.e5.

[118] Rossi M, Altea-Manzano P, Demicco M et al. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature 2022;605:747–753.

[119] Ruan X, Yan W, Cao M et al. Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis. Nat Commun 2024;15:4549.

[120] Ruiu R, Rolih V, Bolli E et al. Fighting breast cancer stem cells through the immune-targeting of the xCT cystine-glutamate antiporter. Cancer Immunol Immunother 2019;68:131–141.

[121] Saito Y, Li L, Coyaud E et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER₊ breast cancer. Nature 2019;569:275–279.

[122] Sarangi P. Role of indoleamine 2, 3-dioxygenase 1 in immunosuppression of breast cancer. Cancer Pathog Ther 2024;2:246–255.

[123] Scales TQ, Smith B, Blanchard LM et al. A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer. Cancer Metab 2024;12:38.

[124] Schulte ML, Fu A, Zhao P et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 2018;24:194–202.

[125] Sennoune SR, Nandagopal GD, Ramachandran S et al. Potent inhibition of Macropinocytosis by Niclosamide in cancer cells: a novel mechanism for the anticancer efficacy for the antihelminthic. Cancers (Basel) 2023;15:759.

[126] Shahnazari M, Bigdeli R, Dashbolaghi A et al. Biochemical and biological evaluation of an L-Asparaginase from isolated Escherichia coli MF-107 as an anti-tumor enzyme on MCF7 cell line. Iran Biomed J 2022;26:279–290.

[127] Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL et al. MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol Cancer 2014;13:239.

[128] Sharma S, Singh B, Mishra AK et al. LAT-1 based primary breast cancer detection by [99m]Tc-labeled DTPA-bismethionine scintimammography: first results using indigenously developed single vial kit preparation. Cancer Biother Radiopharm 2014;29:283–288.

[129] Shen J, Yan L, Liu S et al. Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes. Transl Oncol 2013;6:757–765.

[130] Shen X, Wang G, He H et al. SLC38A5 promotes glutamine metabolism and inhibits cisplatin chemosensitivity in breast cancer. Breast Cancer 2024;31:96–104.

[131] Shi J, Pabon K, Ding R et al. ABCG2 and SLC1A5 functionally interact to rewire metabolism and confer a survival advantage to cancer cells under oxidative stress. J Biol Chem 2024;300:107299.

[132] Soliman H, Khambati F, Han HS et al. A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer. Oncotarget 2018;9:10110–10117.

[133] Strekalova E, Malin D, Good DM et al. Methionine deprivation induces a targetable vulnerability in triple-negative breast cancer cells by enhancing TRAIL Receptor-2 expression. Clin Cancer Res 2015;21:2780–2791.

[134] Sullivan LB, Luengo A, Danai LV et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat Cell Biol 2018;20:782–788.

[135] Sullivan MR, Mattaini KR, Dennstedt EA et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab 2019;29:1410–1421.e4.

[136] Sun N, Zhao X. Argininosuccinate synthase 1, arginine deprivation therapy and cancer management. Front Pharmacol 2022;13:935553.

[137] Sun X, Wang M, Wang M et al. Metabolic reprogramming in triple-negative breast cancer. Front Oncol 2020;10:428.

[138] Switzer CH, Glynn SA, Cheng RY et al. S-Nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer. Mol Cancer Res 2012;10:1203–1215.

[139] Tade FI, Cohen MA, Styblo TM et al. Anti-3-¹⁸F-fACBC (¹⁸F-Fluciclovine) PET/CT of breast cancer: an exploratory study. J Nucl Med 2016;57:1357–1363.

[140] Tajan M, Vousden KH. Dietary approaches to cancer therapy. Cancer Cell 2020;37:767–785.

[141] Tajan M, Hennequart M, Cheung EC et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun 2021;12:366.

[142] Takaku H, Takase M, Abe S et al. In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. Int J Cancer 1992;51:244–249.

[143] Timmerman LA, Holton T, Yuneva M et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 2013;24:450–465.

[144] Tombari C, Zannini A, Bertolio R et al. Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth. Nat Commun 2023;14:6777.

[145] Tornroos R, Tina E, Gothlin Eremo A. SLC7A5 is linked to increased expression of genes related to proliferation and hypoxia in estrogen?receptor?positive breast cancer. Oncol Rep 2022;47:17.

[146] Triplett TA, Garrison KC, Marshall N et al. Reversal of indoleamine 2, 3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat Biotechnol 2018;36:758–764.

[147] Tsuchiya T, Honda H, Oikawa M et al. Oral administration of the amino acids cystine and theanine attenuates the adverse events of S-1 adjuvant chemotherapy in gastrointestinal cancer patients. Int J Clin Oncol 2016;21:1085–1090.

[148] van Geldermalsen M, Wang Q, Nagarajah R et al. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 2016;35:3201–3208.

[149] van Geldermalsen M, Quek LE, Turner N et al. Benzylserine inhibits breast cancer cell growth by disrupting intracellular amino acid homeostasis and triggering amino acid response pathways. BMC Cancer 2018;18:689.

[150] Vidal CM, Ouyang C, Qi Y et al. Arginine regulates HSPA5/BiP translation through ribosome pausing in triple-negative breast cancer cells. Br J Cancer 2023;129:444–454.

[151] Vidula N, Yau C, Rugo HS. Glutaminase (GLS1) gene expression in primary breast cancer. Breast Cancer 2023;30:1079–1084.

[152] Wang Q, Liberti MV, Liu P et al. Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity. Cell Chem Biol 2017;24:55–65.

[153] Wang R, Xiang W, Xu Y et al. Enhanced glutamine utilization mediated by SLC1A5 and GPT2 is an essential metabolic feature of colorectal signet ring cell carcinoma with therapeutic potential. Ann Transl Med 2020a;8:302.

[154] Wang Z, Liu F, Fan N et al. Targeting glutaminolysis: new perspectives to understand cancer development and novel strategies for potential target therapies. Front Oncol 2020b;10:589508.

[155] Wei Z, Liu X, Cheng C et al. Metabolism of amino acids in cancer. Front Cell Dev Biol 2020;8:603837.

[156] Wichmann CW, Burvenich IJG, Guo N et al. Preclinical radiolabeling, in vivo biodistribution and positron emission tomography of a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2. Nucl Med Biol 2023;122–123:108366.

[157] Wicker CA, Hunt BG, Krishnan S et al. Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models. Cancer Lett 2021;502:180–188.

[158] Wu Q, Li J, Sun S et al. YAP/TAZ-mediated activation of serine metabolism and methylation regulation is critical for LKB1-deficient breast cancer progression. Biosci Rep 2017;37:BSR20171072.

[159] Xie G, Zhou B, Zhao A et al. Lowered circulating aspartate is a metabolic feature of human breast cancer. Oncotarget 2015;6:33369–33381.

[160] Xu X, Zhu H, Liu F et al. Dynamic PET/CT imaging of ¹⁸F-(2S, 4R)4-fluoroglutamine in healthy volunteers and oncological patients. Eur J Nucl Med Mol Imaging 2020;47:2280–2292.

[161] Xue C, Li G, Zheng Q et al. Tryptophan metabolism in health and disease. Cell Metab 2023;35:1304–1326.

[162] Yang TS, Lu SN, Chao Y et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer 2010;103:954–960.

[163] Yang WS, SriRamaratnam R, Welsch ME et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014;156:317–331.

[164] Yang J, Zhou Y, Xie S et al. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res 2021a;40:206.

[165] Yang R, Guo Z, Zhao Y et al. Compound 968 reverses adriamycin resistance in breast cancer MCF-7^(ADR) cells via inhibiting P-glycoprotein function independently of glutaminase. Cell Death Discov 2021b;7:204.

[166] Yao S, Janku F, Koenig K et al. Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors. Cancer Med 2022;11:340–347.

[167] Yoo HC, Yu YC, Sung Y et al. Glutamine reliance in cell metabolism. Exp Mol Med 2020;52:1496–1516.

[168] You M, Xie Z, Zhang N et al. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023;8:196.

[169] Zhang X, Bai W. Repression of phosphoglycerate dehydrogenase sensitizes triple-negative breast cancer to doxorubicin. Cancer Chemother Pharmacol 2016;78:655–659.

[170] Zhang Y, Lindstrom S, Kraft P et al. Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer. J Natl Cancer Inst 2025;117:40–48.

[171] Zhou LY, Shi YH, Jia YS et al. Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane. Chronic Dis Transl Med 2015;1:27–35.

[172] Zhou X, Zheng W, Nagana Gowda GA et al. 1, 25-Dihydroxyvitamin D inhibits glutamine metabolism in Harvey-ras transformed MCF10A human breast epithelial cell. J Steroid Biochem Mol Biol 2016;163:147–156.

[173] Zhou R, Pantel AR, Li S et al. [¹⁸F](2S, 4R)4-Fluoroglutamine PET detects glutamine pool size changes in triple-negative breast cancer in response to glutaminase inhibition. Cancer Res 2017;77:1476–1484.

RIGHTS & PERMISSIONS

The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.