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Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes

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Abstract

Oncogenic metabolic reprogramming impacts the abundance of key metabolites that regulate signaling and epigenetics. Metabolic vulnerability in the cancer cell is evident from the Warburg effect. The research on metabolism in the progression and survival of breast cancer (BC) is under focus. Oncogenic signal activation and loss of tumor suppressor are important regulators of tumor cell metabolism. Several intrinsic and extrinsic factors contribute to metabolic reprogramming. The molecular mechanisms underpinning metabolic reprogramming in BC are extensive and only partially defined. Various signaling pathways involved in the metabolism play a significant role in the modulation of BC. Notably, PI3K/AKT/mTOR pathway, lactate-ERK/STAT3 signaling, loss of the tumor suppressor Ras, Myc, oxidative stress, activation of the cellular hypoxic response and acidosis contribute to different metabolic reprogramming phenotypes linked to enhanced glycolysis. The alterations in mitochondrial genes have also been elaborated upon along with their functional implications. The outcome of these active research areas might contribute to the development of novel therapeutic interventions and the remodeling of known drugs.

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References

  1. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets and Therapy. 2019;11:151.

    PubMed  Google Scholar 

  2. Sung, H., J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 2021. 71(3): p. 209–249.

  3. Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J Clin. 2011;61:409–18.

    PubMed  Google Scholar 

  4. Sung H, Ferlay J, Siegel RL. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  5. Łukasiewicz S, Czeczelewski M, Forma A. Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies-an updated review. Cancers. 2021;13(17):4287.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vazquez A, Kamphorst JJ, Markert EK, Schug ZT, Tardito S, Gottlieb E. Cancer metabolism at a glance. J Cell Sci. 2016;129(18):3367–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Landor SK-J, Mutvei AP, Mamaeva V, Jin S, Busk M, Borra R, et al. Hypo-and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms. Proc Natl Acad Sci. 2011;108(46):18814–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168(4):657–69.

    Article  CAS  PubMed  Google Scholar 

  9. Anderson G. Type I diabetes pathoetiology and pathophysiology: roles of the gut microbiome, pancreatic cellular interactions, and the ‘bystander’ activation of memory CD8+ T cells. Int J Mol Sci. 2023;24(4):3300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Formentini L, Martínez-Reyes I, Cuezva JM. The mitochondrial bioenergetic capacity of carcinomas. IUBMB Life. 2010. https://doi.org/10.1002/iub.352.

    Article  PubMed  Google Scholar 

  11. Yadav UP, Singh T, Kumar P, Sharma P, Kaur H, Sharma S, et al. Metabolic adaptations in cancer stem cells. Front Oncol. 2020;10:1010.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zheng J. Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation. Oncol Lett. 2012;4(6):1151–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Végran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Can Res. 2011;71(7):2550–60.

    Article  Google Scholar 

  14. Rothberg, J.M., K.M. Bailey, J.W. Wojtkowiak, Y. Ben-Nun, M. Bogyo, E. Weber, et al., Acid-mediated tumor proteolysis: contribution of cysteine cathepsins. Neoplasia, 2013. 15(10): p. 1125-IN9.

  15. Hu Y, Lu W, Chen G, Wang P, Chen Z, Zhou Y, et al. K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res. 2012;22(2):399–412.

    Article  CAS  PubMed  Google Scholar 

  16. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11(5):325–37.

    Article  CAS  PubMed  Google Scholar 

  17. Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. 2021;10(5):1056.

    CAS  Google Scholar 

  18. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. King, A., M. Selak, and, and E. Gottlieb, Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene, 2006. 25(34): p. 4675–4682.

  20. Albadari, N., S. Deng, and W. Li, The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. 2019. 14(7): p. 667–682.

  21. Laurenti G, Tennant DA. Isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH): three players for one phenotype in cancer? Biochem Soc Trans. 2016;44(4):1111–6.

    Article  CAS  PubMed  Google Scholar 

  22. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S-H, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tarrado-Castellarnau M, de Atauri P, Cascante M. Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. 2016;7(38):62726–53.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer Nature Reviews Disease Primers. 2019;5(1):66.

    Article  PubMed  Google Scholar 

  25. Dewan K, Mandal A. Surrogate molecular classification of breast carcinoma: A classification in need or a dilemma indeed. Oncology Journal of India. 2020;4(3):79–86.

    Article  Google Scholar 

  26. Wang Z, Jiang Q, Dong C. Metabolic reprogramming in triple-negative breast cancer. Cancer Biol Med. 2020;17(1):44–59.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Holloway, R.W. and P.A. Marignani, Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer. Cancers (Basel), 2021. 13(12), 2922.

  28. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shin E, Koo JS. Glucose metabolism and glucose transporters in breast cancer. Front Cell Dev Biol. 2021;9: 728759.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Long J-P, Li X-N, Zhang F. Targeting metabolism in breast cancer: How far we can go? World journal of clinical oncology. 2016;7(1):122.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Choi J, Jung W-H, Koo JS. Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology. 2013;80(1):41–52.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang, Y., Q. Li, Z. Huang, and B. Li, Targeting glucose metabolism enzymes in cancer treatment: current and emerging strategies. Cancers. 2022. 14(19), 4568.

  33. Ko Y-H, Lin Z, Flomenberg N, Pestell RG, Howell A, Sotgia F, et al. Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: implications for preventing chemotherapy resistance. Cancer Biol Ther. 2011;12(12):1085–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ko B-H, Paik J-Y, Jung K-H, Lee K-H. 17β-Estradiol augments 18F-FDG uptake and glycolysis of T47D breast cancer cells via membrane-initiated rapid PI3K–Akt activation. J Nucl Med. 2010;51(11):1740–7.

    Article  CAS  PubMed  Google Scholar 

  35. Fhu CW, Ali A. Fatty Acid Synthase: An Emerging Target in Cancer. Molecules. 2020;25(17):3935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Iqbal MA, Bamezai RN. Resveratrol inhibits cancer cell metabolism by down regulating pyruvate kinase M2 via inhibition of mammalian target of rapamycin. PLoS ONE. 2012;7(5): e36764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luo S, Jiang Y, Anfu Z, Zhao Y, Wu X, Li M, et al. Targeting hypoxia-inducible factors for breast cancer therapy: A narrative review. Front Pharmacol. 2022;13:1064661.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Miricescu D, Totan A, Stanescu-Spinu I-I, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR signaling pathway in breast cancer: From molecular landscape to clinical aspects. Int J Mol Sci. 2020;22(1):173.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kulkoyluoglu-Cotul E, Arca A, Madak-Erdogan Z. Crosstalk between estrogen signaling and breast cancer metabolism. Trends Endocrinol Metab. 2019;30(1):25–38.

    Article  CAS  PubMed  Google Scholar 

  40. Lim, W., B. Mayer, and T. Pawson, Cell signaling. 2014: Taylor & Francis.

  41. Bhaskar PT, Nogueira V, Patra KC, Jeon S-M, Park Y, Robey RB, et al. mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3β inhibition. Mol Cell Biol. 2009;29(18):5136–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pande M, Bondy ML, Do K-A, Sahin AA, Ying J, Mills GB, et al. Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival. Breast Cancer Res Treat. 2014;147(2):381–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):1–12.

    Article  Google Scholar 

  44. Sobral-Leite M, Salomon I, Opdam M, Kruger DT, Beelen KJ, van der Noort V, et al. Cancer-immune interactions in ER-positive breast cancers: PI3K pathway alterations and tumor-infiltrating lymphocytes. Breast Cancer Res. 2019;21(1):1–12.

    Article  CAS  Google Scholar 

  45. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22(20):7004–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roberts D, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 2015;22(2):248–57.

    Article  CAS  PubMed  Google Scholar 

  47. Brown RS, Wahl RL. Overexpression of glut-1 glucose transporter in human breast cancer an immunohistochemical study. Cancer. 1993;72(10):2979–85.

    Article  CAS  PubMed  Google Scholar 

  48. Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metabolism. 2014;2(1):1–9.

    Article  Google Scholar 

  49. Liu W-S, Chan S-H, Chang H-T, Li G-C, Tu Y-T, Tseng H-H, et al. Isocitrate dehydrogenase 1–snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability. Breast Cancer Res. 2018;20(1):1–17.

    Article  Google Scholar 

  50. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.

    Article  CAS  PubMed  Google Scholar 

  51. Yang L, Hou Y, Yuan J, Tang S, Zhang H, Zhu Q, et al. Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways. Oncotarget. 2015;6(28):25755.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kotowski K, Rosik J, Machaj F, Supplitt S, Wiczew D, Jabłońska K, et al. Role of PFKFB3 and PFKFB4 in cancer: genetic basis, impact on disease development/progression, and potential as therapeutic targets. Cancers. 2021;13(4):909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu Y, Wang R, Zhang L, Li J, Lou K, Shi B. The lipid metabolism gene FTO influences breast cancer cell energy metabolism via the PI3K/AKT signaling pathway. Oncol Lett. 2017;13(6):4685–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tseng C-W, Kuo W-H, Chan S-H, Chan H-L, Chang K-J, Wang L-H. Transketolase regulates the metabolic switch to control breast cancer cell metastasis via the α-ketoglutarate signaling pathway. Can Res. 2018;78(11):2799–812.

    Article  CAS  Google Scholar 

  55. Miao P, Sheng S, Sun X, Liu J, Huang G. Lactate dehydrogenase A in cancer: a promising target for diagnosis and therapy. IUBMB Life. 2013;65(11):904–10.

    Article  CAS  PubMed  Google Scholar 

  56. He W, Miao FJ-P, Lin DC-H, Schwandner RT, Wang Z, Gao J, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429(6988):188–93.

    Article  CAS  PubMed  Google Scholar 

  57. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci. 2011;108(49):19611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B, et al. Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 2018;17(4):428–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zaugg, M., P.-H. Lou, E. Lucchinetti, M. Gandhi, and A.S. Clanachan, Postconditioning with Intralipid emulsion protects against reperfusion injury in post-infarct remodeled rat hearts by activation of ROS-Akt/Erk signaling. Translational Research, 2017. 186: p. 36–51. e2.

  60. Tkach, M., C. Rosemblit, M.A. Rivas, C.J. Proietti, M.C. Díaz Flaqué, M.F. Mercogliano, et al., p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocr Relat Cancer, 2013. 20(2): p. 197–212.

  61. Bromberg J. Stat proteins and oncogenesis. J Clin Investig. 2002;109(9):1139–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Epling-Burnette P, Liu JH, Catlett-Falcone R, Turkson J, Oshiro M, Kothapalli R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Investig. 2001;107(3):351–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li R, Hebert JD, Lee TA, Xing H, Boussommier-Calleja A, Hynes RO, et al. Macrophage-secreted TNFα and TGFβ1 influence migration speed and persistence of cancer cells in 3D tissue culture via independent pathways. Can Res. 2017;77(2):279–90.

    Article  CAS  Google Scholar 

  64. Yao A, Xiang Y, Si YR, Fan LJ, Li JP, Li H, et al. PKM2 promotes glucose metabolism through a let-7a-5p/Stat3/hnRNP-A1 regulatory feedback loop in breast cancer cells. J Cell Biochem. 2019;120(4):6542–54.

    Article  CAS  PubMed  Google Scholar 

  65. David CJ, Chen M, Assanah M, Canoll P, Manley JL. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature. 2010;463(7279):364–8.

    Article  CAS  PubMed  Google Scholar 

  66. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell. 2012;149(6):1269–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang L, Zhang S, Wang X. The metabolic mechanisms of breast cancer metastasis. Front Oncol. 2021;10: 602416.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci. 2011;108(39):16259–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hsu C-C, Tseng L-M, Lee H-C. Role of mitochondrial dysfunction in cancer progression. Exp Biol Med. 2016;241(12):1281–95.

    Article  CAS  Google Scholar 

  70. Karlsson, R., E. Pedersen, Z. Wang, and C. Brakebusch, Rho GTPase function in tumorigenesis. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2009. 1796(2): p. 91–98.

  71. Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4(1):1–15.

    Article  Google Scholar 

  72. Turgeon M-O, Perry NJ, Poulogiannis G. DNA damage, repair, and cancer metabolism. Front Oncol. 2018;8:15.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5(9): a012716.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Aird KM, Worth AJ, Snyder NW, Lee JV, Sivanand S, Liu Q, et al. ATM couples replication stress and metabolic reprogramming during cellular senescence. Cell Rep. 2015;11(6):893–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Turgeon M-O, Perry NJS, Poulogiannis G. DNA damage, repair, and cancer metabolism. Front Oncol. 2018. https://doi.org/10.3389/fonc.2018.00015.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Biswas DK, Iglehart JD. Linkage between EGFR family receptors and nuclear factor kappaB (NF-κB) signaling in breast cancer. J Cell Physiol. 2006;209(3):645–52.

    Article  CAS  PubMed  Google Scholar 

  77. Shi J, Wei PK. Interleukin-8: A potent promoter of angiogenesis in gastric cancer. Oncol Lett. 2016;11(2):1043–50.

    Article  CAS  PubMed  Google Scholar 

  78. Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, et al. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2*. J Biol Chem. 2003;278(10):8508–15.

    Article  CAS  PubMed  Google Scholar 

  79. Rizzo, M., L. Varnier, G. Pezzicoli, M. Pirovano, L. Cosmai, and C. Porta, IL-8 and its role as a potential biomarker of resistance to anti-angiogenic agents and immune checkpoint inhibitors in metastatic renal cell carcinoma. Frontiers in Oncology, 2022: p. 12, 4411.

  80. Sudarshan S, Sourbier C, Kong H-S, Block K, Romero VV, Yang Y, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and HIF-1α stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. 2009;29(15):4080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shanmugasundaram K, Nayak B, Shim E-H, Livi CB, Block K, Sudarshan S. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling. J Biol Chem. 2014;289(35):24691–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Korherr C, Gille H, Schäfer R, Koenig-Hoffmann K, Dixelius J, Egland KA, et al. Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. Proc Natl Acad Sci. 2006;103(11):4240–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kamdje AHN, Etet PFS, Vecchio L, Muller JM, Krampera M, Lukong KE. Signaling pathways in breast cancer: therapeutic targeting of the microenvironment. Cell Signal. 2014;26(12):2843–56.

    Article  Google Scholar 

  84. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015;12(8):445–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294(5545):1337–40.

    Article  CAS  PubMed  Google Scholar 

  86. Funasaka T, Hogan V, Raz A. Phosphoglucose isomerase/autocrine motility factor mediates epithelial and mesenchymal phenotype conversions in breast cancer. Can Res. 2009;69(13):5349–56.

    Article  CAS  Google Scholar 

  87. Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.

    Article  CAS  PubMed  Google Scholar 

  88. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci. 2004;101(10):3329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Andrade-Vieira R, Xu Z, Colp P, Marignani PA. Loss of LKB1 expression reduces the latency of ErbB2-mediated mammary gland tumorigenesis, promoting changes in metabolic pathways. PLoS ONE. 2013;8(2): e56567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang Z-G, Zhang H-S, Sun H-L, Liu H-Y, Liu M-Y, Zhou Z. KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming. Exp Cell Res. 2019;379(2):182–90.

    Article  CAS  PubMed  Google Scholar 

  91. Boland M, Chourasia A, Macleod K. Mitochondrial Dysfunction in Cancer. Front Oncol. 2013. https://doi.org/10.3389/fonc.2013.00292.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Lamb R, Ablett MP, Spence K, Landberg G, Sims AH, Clarke RB. Wnt pathway activity in breast cancer sub-types and stem-like cells. PLoS ONE. 2013;8(7): e67811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jeng K-S, Sheen I-S, Jeng W-J, Yu M-C, Hsiau H-I, Chang F-Y. High expression of Sonic Hedgehog signaling pathway genes indicates a risk of recurrence of breast carcinoma. Onco Targets Ther. 2014;7:79.

    Google Scholar 

  94. Hu J, Li T, Du S, Chen Y, Wang S, Xiong F, et al. The MAPK signaling pathway mediates the GPR91-dependent release of VEGF from RGC-5 cells. Int J Mol Med. 2015;36(1):130–8.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Huang Q, Cao H, Zhan L, Sun X, Wang G, Li J, et al. Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Lett. 2017;403:108–18.

    Article  CAS  PubMed  Google Scholar 

  96. Xie Q, Wu Q, Horbinski CM, Flavahan WA, Yang K, Zhou W, et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci. 2015;18(4):501–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ma Y, Wang L, Jia R. The role of mitochondrial dynamics in human cancers. Am J Cancer Res. 2020;10(5):1278.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Bushel PR, Ward J, Burkholder A, Li J, Anchang B. Mitochondrial-nuclear epistasis underlying phenotypic variation in breast cancer pathology. Sci Rep. 2022;12(1):1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kim TW, Kim B, Kim JH, Kang S, Park S-B, Jeong G, et al. Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer. BMC Cancer. 2013;13(1):502.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Chang S, Singh L, Thaker K, Abedi S, Singh MK, Patel TH, et al. Altered retrograde signaling patterns in breast cancer cells cybrids with H and J mitochondrial DNA haplogroups. Int J Mol Sci. 2022;23(12):6687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. El-Sahli S, Wang L. Cancer stem cell-associated pathways in the metabolic reprogramming of breast cancer. Int J Mol Sci. 2020;21(23):9125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Oku Y, Nishiya N, Shito T, Yamamoto R, Yamamoto Y, Oyama C, et al. Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers. FEBS Open Bio. 2015;5:542–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ma J, Fan Z, Tang Q, Xia H, Zhang T, Bi F. Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer. Cell Death Dis. 2020;11(7):530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 2014;16(4):357–66.

    Article  CAS  PubMed  Google Scholar 

  105. Ishikawa T, Hosaka YZ, Beckwitt C, Wells A, Oltvai ZN, Warita K. Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics. Oncotarget. 2018;9(50):29304.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wang P, Gong Y, Guo T, Li M, Fang L, Yin S, et al. Activation of Aurora A kinase increases YAP stability via blockage of autophagy. Cell Death Dis. 2019;10(6):432.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Turkson J, Zhang S, Mora LB, Burns A, Sebti S, Jove R. A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J Biol Chem. 2005;280(38):32979–88.

    Article  CAS  PubMed  Google Scholar 

  108. Kim JW, Gautam J, Kim JE, Kim J, Kang KW. Inhibition of tumor growth and angiogenesis of tamoxifen-resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor. Oncol Lett. 2019;17(4):3981–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chen K-F, Tai W-T, Hsu C-Y, Huang J-W, Liu C-Y, Chen P-J, et al. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem. 2012;55:220–7.

    Article  CAS  PubMed  Google Scholar 

  110. Srirangam A, Milani M, Mitra R, Guo Z, Rodriguez M, Kathuria H, et al. The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin. J Thorac Oncol. 2011;6(4):661–70.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Park S, Chang C-Y, Safi R, Liu X, Baldi R, Jasper JS, et al. ERRα-regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer. Cell Rep. 2016;15(2):323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu T, Harder BG, Wong PK, Lang JE, Zhang DD. Oxidative stress, mammospheres and Nrf2–new implication for breast cancer therapy? Mol Carcinog. 2015;54(11):1494–502.

    Article  CAS  PubMed  Google Scholar 

  113. Park S, Safi R, Liu X, Baldi R, Liu W, Liu J, et al. Inhibition of ERRα prevents mitochondrial pyruvate uptake exposing NADPH-generating pathways as targetable vulnerabilities in breast cancer. Cell Rep. 2019;27(12):3587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Feldinger K, Kong A. Profile of neratinib and its potential in the treatment of breast cancer. Breast Cancer: Targets and Therapy. 2015;7:147.

    PubMed  Google Scholar 

  115. Barry JB, Giguere V. Epidermal growth factor–induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor α. Can Res. 2005;65(14):6120–9.

    Article  CAS  Google Scholar 

  116. Madan B, Ke Z, Harmston N, Ho SY, Frois A, Alam J, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016;35(17):2197–207.

    Article  CAS  PubMed  Google Scholar 

  117. Furuya K, Sasaki A, Tsunoda Y, Tsuji M, Udaka Y, Oyamada H, et al. Eribulin upregulates miR-195 expression and downregulates Wnt3a expression in non-basal-like type of triple-negative breast cancer cell MDA-MB-231. Hum Cell. 2016;29:76–82.

    Article  CAS  PubMed  Google Scholar 

  118. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci. 2013;110(50):20224–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tam BY, Chiu K, Chung H, Bossard C, Nguyen JD, Creger E, et al. The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models. Cancer Lett. 2020;473:186–97.

    Article  CAS  PubMed  Google Scholar 

  120. Katoh M. Antibody-drug conjugate targeting protein tyrosine kinase 7, a receptor tyrosine kinase-like molecule involved in WNT and vascular endothelial growth factor signaling: effects on cancer stem cells, tumor microenvironment and whole-body homeostasis. Annals Transl Med. 2017;5(23):462.

    Article  Google Scholar 

  121. Fischer MM, Cancilla B, Yeung VP, Cattaruzza F, Chartier C, Murriel CL, et al. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. Sci Adv. 2017;3(6): e1700090.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Grzybowska-Szatkowska L, Ślaska B. Mitochondrial NADH dehydrogenase polymorphisms are associated with breast cancer in Poland. J Appl Genet. 2014;55(2):173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Czarnecka AM, Klemba A, Krawczyk T, Zdrozny M, Arnold RS, Bartnik E, et al. Mitochondrial NADH-dehydrogenase polymorphisms as sporadic breast cancer risk factor. Oncol Rep. 2010;23(2):531–5.

    CAS  PubMed  Google Scholar 

  124. Canter JA, Kallianpur AR, Parl FF, Millikan RC. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Can Res. 2005;65(17):8028–33.

    Article  CAS  Google Scholar 

  125. Darvishi K, Sharma S, Bhat AK, Rai E, Bamezai R. Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer. Cancer Lett. 2007;249(2):249–55.

    Article  CAS  PubMed  Google Scholar 

  126. Czarnecka AM, Krawczyk T, Plak K, Klemba A, Zdrozny M, Arnold RS, et al. Mitochondrial genotype and breast cancer predisposition. Oncol Rep. 2010;24(6):1521–34.

    CAS  PubMed  Google Scholar 

  127. Tan D-J, Bai R-K, Wong L-JC. Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Can Res. 2002;62(4):972–6.

    CAS  Google Scholar 

  128. Gallardo ME, Moreno-Loshuertos R, López C, Casqueiro M, Silva J, Bonilla F, et al. m 6267G> A: a recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors. Hum Mutat. 2006;27(6):575–82.

    Article  CAS  PubMed  Google Scholar 

  129. Girolimetti G, Marchio L, De Leo A, Mangiarelli M, Amato LB, Zanotti S, et al. Mitochondrial DNA analysis efficiently contributes to the identification of metastatic contralateral breast cancers. J Cancer Res Clin Oncol. 2021;147(2):507–16.

    Article  CAS  PubMed  Google Scholar 

  130. Grzybowska-Szatkowska L, Ślaska B, Rzymowska J, Brzozowska A, Floriańczyk B. Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer. Mol Med Rep. 2014;10(4):1772–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kalia M. Personalized oncology: Recent advances and future challenges. Metabolism. 2013;62:S11–4.

    Article  CAS  PubMed  Google Scholar 

  132. Jayasekera LP, Ranasinghe R, Senathilake KS, Kotelawala JT, de Silva K, Abeygunasekara PH, et al. Mitochondrial genome in sporadic breast cancer: A case control study and a proteomic analysis in a Sinhalese cohort from Sri Lanka. PLoS ONE. 2023;18(2): e0281620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jackson SE, Chester JD. Personalised cancer medicine. Int J Cancer. 2015;137(2):262–6.

    Article  CAS  PubMed  Google Scholar 

  134. Gambardella V, Tarazona N, Cejalvo JM, Lombardi P, Huerta M, Roselló S, et al. Personalized medicine: recent progress in cancer therapy. Cancers. 2020;12(4):1009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Manzari MT, Shamay Y, Kiguchi H, Rosen N, Scaltriti M, Heller DA. Targeted drug delivery strategies for precision medicines. Nat Rev Mater. 2021;6(4):351–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the Central University of Punjab for providing infrastructure and facilities, University Grant Commission, New Delhi, for Junior Research Fellowship (JRF) to Ruthuparna Malayil for PhD, Council of Scientific and Industrial Research (CSIR), New Delhi, for Senior Research Fellowship (SRF) to Yogita Chhichholiya and Tashvinder Singh, and Science and Engineering Research Board (SERB) to Harsh Vikram Singh for Project Assistantship. DST-FIST grant (SR/FST/LS-I/2017/49) to the Department of Human Genetics and Molecular Medicine, Central University of Punjab, is acknowledged with thanks.

Funding

Financial support to Rhuthuparna Malayil (Award No- KL1216200313) from University Grant Commission, India, Yogita Chhichholiya (Award No- 09/1051(0038)/2019-EMR-1) and Tashvinder Singh (Award No- 09/1051(0042)/2019-EMR-1) from Council of Scientific and Industrial Research (CSIR) India, and Harsh Vikram Singh (SRG/2021/001806) for Project Assistantship from Science and Engineering Research Board (SERB) is highly acknowledged.

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Authors and Affiliations

  1. Department of Human Genetics and Molecular Medicine, Central University of Punjab Bathinda, Punjab, India

    Rhuthuparna Malayil, Yogita Chhichholiya, Tashvinder Singh, Sandeep Singh & Anjana Munshi

  2. Indian Council of Medical Research, New Delhi, India

    Kanika Vasudeva

  3. Department of Orthopedics, All India Institute of Medical Sciences, Bathinda, India

    Harsh Vikram Singh

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  1. Rhuthuparna Malayil
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  2. Yogita Chhichholiya
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  3. Kanika Vasudeva
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  4. Harsh Vikram Singh
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  5. Tashvinder Singh
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  6. Sandeep Singh
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  7. Anjana Munshi
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Contributions

Anjana Munshi and Sandeep Singh conceptualized the idea of the review. Rhuthuparna malayil, Yogita Chhichholiya, Kanika Vasudeva, Harsh Vikram Singh, and Tashvinder Singh curated the data and prepared the draft. Anjana Munshi and Sandeep Singh critically revised and edited the manuscript.

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Correspondence to Sandeep Singh or Anjana Munshi.

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Malayil, R., Chhichholiya, Y., Vasudeva, K. et al. Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes. Med Oncol 40, 174 (2023). https://doi.org/10.1007/s12032-023-02037-2

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