Nuances of PFKFB3 signaling in breast cancer

Published:January 14, 2022DOI:


      • Cellular metabolism, survival, and proliferation are linked with PFKFB3 activity.
      • Hormonal status drives PFKFB3 activity in breast cancer.
      • PFKFB3 links external stimuli to cellular responses via kinase cascades.
      • Anti-PFKFB3 therapy has a suppressive effect over cell functions due to various mechanisms.


      The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that supports glucose catabolism. PFKFB3 produces the signaling molecule fructose-2,6-biphosphate (F2,6BP), which activates the second gatekeeper in glycolysis, 6-phosphofructo-1-kinase (PFK-1), and favors the Warburg phenotype. Transcriptional and post-transcriptional processes regulate the abundance and phosphorylation of PFKFB3 in cells, and its activation has been implicated in the progression of several types of cancer. PFKFB3 is important for sustaining glycolysis in the tumorigenesis environment even under unfavorable conditions, thereby promoting metabolic reprogramming, cell proliferation, DNA repair, and drug resistance. Despite its heterogeneous phenotype, breast cancer has unique characteristics that drive the constitutive and inducible expression of PFKFB3 in this opportunistic glycolytic shift. This enzyme is a point of convergence of multiple exogenous and endogenous growth-promoting and oncogenic signaling pathways, especially kinase cascades. The present review summarizes advances in in vitro and in vivo therapy studies that focus on PFKFB3 and the interplay between hormone receptor status and the underlying essential signal transduction system in breast cancer metabolic remodeling.

      Graphical Abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal


      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Simon-Molas H.
        • Calvo-Vidal M.N.
        • Castaño E.
        Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition.
        FEBS Letters. 2016; (Published online)
        • Fadaka A.
        • Ajiboye B.
        • Ojo O.
        • Adewale O.
        • Olayide I.
        • Emuowhochere R.
        Biology of glucose metabolization in cancer cells.
        Journal of Oncological Sciences. 2017; (Published online)
        • Okar D.A.
        • Lange A.J.
        • Manzano À.
        • Navarro-Sabatè A.
        • Riera L.
        • Bartrons R.
        PFK-2/FBPase-2: Maker and breaker of the essential biofactor fructose-2,6-bisphosphate.
        Trends in Biochemical Sciences. 2001; (Published online)
      1. Ma H., Zhang J., Zhou L., c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3. Cell Reports. Published online 2020. doi:10.1016/j.celrep.2020.03.005

        • Novellasdemunt L.
        • Obach M.
        • Millán-ariño L.
        Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells.
        Biochemical Journal. 2012; (Published online)
        • Rider M.H.
        • Bertrand L.
        • Vertommen D.
        • Michels P.A.
        • Rousseau G.G.
        Hue L. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Head-to-head with a bifunctional enzyme that controls glycolysis.
        Biochemical Journal. 2004; (Published online)
        • Li F.L.
        • Liu J.P.
        • Bao R.X.
        Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.
        Nature Communications. Published online. 2018;
        • Yan S.
        • Wei X.
        • Xu S.
        6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 spatially mediates autophagy through the AMPK signaling pathway.
        Oncotarget. 2017; (Published online)
        • Li H.M.
        • Yang J.G.
        • Liu Z.J.
        Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma.
        Journal of Experimental and Clinical Cancer Research. 2017; (Published online)
      2. Richardson D.A., Sritangos P., James A.D., Sultan A., Bruce J.I.E. Metabolic regulation of calcium pumps in pancreatic cancer: role of phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3). Cancer & Metabolism. Published online 2020. doi:10.1186/s40170-020-0210-2

        • Minchenko O.
        • Opentanova I.
        • Caro J.
        Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase gene family (PFKFB-1-4) expression in vivo.
        FEBS Letters. 2003; (Published online)
        • Obach M.
        • Navarro-Sabaté À.
        • Caro J.
        6-Phosphofructo-2-kinase (pfkfb3) Gene Promoter Contains Hypoxia-inducible Factor-1 Binding Sites Necessary for Transactivation in Response to Hypoxia.
        Journal of Biological Chemistry. 2004; 279: 53562-53570
        • Bando H.
        • Atsumi T.
        • Nishio T.
        Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer.
        Clinical Cancer Research. 2005; (Published online)
        • Novellasdemunt L.
        • Bultot L.
        • Manzano A.
        PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli.
        Biochemical Journal. Published online. 2013;
        • Yamamoto T.
        • Takano N.
        • Ishiwata K.
        Reduced methylation of PFKFB3 in cancer cells shunts glucose towards the pentose phosphate pathway.
        Nature Communications. 2014; (Published online)
      3. Tudzarova S., Colombo S.L., Stoeber K., Carcamo S., Williams G.H., Moncada S. Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-β-TrCP, sequentially regulate glycolysis during the cell cycle. Proceedings of the National Academy of Sciences of the United States of America. Published online 2011. doi:10.1073/pnas.1102247108

        • Lu C.
        • Qiao P.
        • Sun Y.
        • Ren C.
        • Yu Z.
        Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer.
        Clinical and Translational Medicine. 2021; 11: e400
        • Doménech E.
        • Maestre C.
        • Esteban-Martínez L.
        AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest.
        Nature Cell Biology. 2015; (Published online)
        • Warburg O.
        • Wind F.
        • Negelein E.
        The metabolism of tumors in the body.
        Journal of General Physiology. 1927; (Published online)
        • Hanahan D.
        • Weinberg R.A.
        Hallmarks of cancer: The next generation.
        Cell. 2011; (Published online)
        • Liberti M.V.
        • Locasale J.W.
        The Warburg Effect: How Does it Benefit Cancer Cells?.
        Trends in Biochemical Sciences. 2016; (Published online)
        • Atsumi T.
        • Chesney J.
        • Metz C.
        High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers.
        Cancer Research. 2002; (Published online)
      4. Chen L., Zhao J., Tang Q., PFKFB3 Control of Cancer Growth by Responding to Circadian Clock Outputs. Scientific Reports. Published online 2016. doi:10.1038/srep24324

        • Gu M.
        • Li L.
        • Zhang Z.
        PFKFB3 promotes proliferation, migration and angiogenesis in nasopharyngeal carcinoma.
        Journal of Cancer. 2017; (Published online)
        • Li X.
        • Liu J.
        • Qian L.
        Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy.
        Molecular and Cellular Biochemistry. 2018; (Published online)
      5. Shi W.K., Zhu X.D., Wang C.H., PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT article. Cell Death and Disease. Published online 2018. doi:10.1038/s41419-018-0435-y

        • Mondal S.
        • Roy D.
        • Sarkar Bhattacharya S.
        Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.
        International Journal of Cancer. 2019; (Published online)
        • Matsumoto K.
        • Noda T.
        • Kobayashi S.
        Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma.
        Cancer letters. 2021; 500: 29-40
      6. Yalcin A., Clem B.F., Imbert-Fernandez Y., 6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27. Cell Death and Disease. Published online 2014. doi:10.1038/cddis.2014.292

        • Romero-Garcia S.
        • Moreno-Altamirano M.M.B.
        • Prado-Garcia H.
        • Sánchez-García F.J.
        Lactate contribution to the tumor microenvironment: Mechanisms, effects on immune cells and therapeutic relevance.
        Frontiers in Immunology. 2016; (Published online)
        • Wang Y.
        • Qu C.
        • Liu T.
        • Wang C.
        PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action, current developments, and structure-activity relationships.
        European Journal of Medicinal Chemistry. 2020; (Published online)
      7. O'Neal J., Clem A., Reynolds L., Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer. Breast Cancer Research and Treatment. Published online 2016. doi:10.1007/s10549-016-3968-8

        • Maher J.C.
        • Krishan A.
        • Lampidis T.J.
        Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions.
        Cancer Chemotherapy and Pharmacology. 2004; (Published online)
        • Zhu W.
        • Ye L.
        • Zhang J.
        PFK15, a small molecule inhibitor of PFKFB3, induces cell cycle arrest, apoptosis and inhibits invasion in gastric cancer.
        PLoS ONE. 2016; (Published online)
      8. Tapolsky G.H., Chand P. PFKFB3 inhibitor and methods of use as an anti-cancer therapeutic. Published online 2017.

        • Redman R.A.
        • Pohlmann P.R.
        • Kurman M.R.
        • Tapolsky G.
        • Chesney J.A.
        A phase I, dose-escalation, multi-center study of PFK-158 in patients with advanced solid malignancies explores a first-in-man inhbibitor of glycolysis.
        Journal of Clinical Oncology. 2015; (Published online)
        • Gustafsson N.M.S.
        • Färnegårdh K.
        • Bonagas N.
        Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination.
        Nature Communications. Published online. 2018;
        • Li S.
        • Dai W.
        • Mo W.
        By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma.
        International Journal of Cancer. 2017; (Published online)
      9. Conradi L.C., Brajic A., Cantelmo A.R., Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. Angiogenesis. Published online 2017. doi:10.1007/s10456-017-9573-6

      10. Murár M., Horvathová J., Moravčík R., Addová G., Zeman M., Boháč A. Synthesis of glycolysis inhibitor (E)-3-(pyridin-3-yl)-1-(pyridin-4-yl)prop-2-en-1-one (3PO) and its inhibition of HUVEC proliferation alone or in a combination with the multi-kinase inhibitor sunitinib. Chemical Papers. Published online 2018. doi:10.1007/s11696-018-0548-x

        • Zhang J.
        • Xue W.
        • Xu K.
        Dual inhibition of PFKFB3 and VEGF normalizes tumor vasculature, reduces lactate production, and improves chemotherapy in glioblastoma: Insights from protein expression profiling and MRI.
        Theranostics. 2020; (Published online)
        • Zhu Y.
        • Lu L.
        • Qiao C.
        Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor.
        Oncogene. Published online. 2018;
      11. Feng Y., Wu L. mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival. Biochemical and Biophysical Research Communications. Published online 2017. doi:10.1016/j.bbrc.2017.01.031

      12. Liu X., Zhao Y., Zhang E., Yan H., Lv N., Cai Z. The synergistic effect of PFK15 with metformin exerts anti-myeloma activity via PFKFB3. Biochemical and Biophysical Research Communications. Published online 2019. doi:10.1016/j.bbrc.2019.05.136

      13. Wang Y., Tang S., Wu Y., Upregulation of 6-phosphofructo-2-kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex. IUBMB Life. Published online 2020. doi:10.1002/iub.2232

        • Lea M.A.
        • Guzman Y.
        • Desbordes C.
        Inhibition of growth by combined treatment with inhibitors of lactate dehydrogenase and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3.
        Anticancer Research. 2016; (Published online)
      14. Sengupta S., Sevigny C.M., Liu X., Jin L., Pohlmann P.R., Clarke R. Abstract 907: Targeting glycolysis enzyme, PFKFB3, in endocrine therapy resistant breast cancers. In:; 2018. doi:10.1158/1538-7445.am2018-907

        • Xiao Y.
        • Jin L.
        • Deng C.
        Inhibition of PFKFB3 induces cell death and synergistically enhances chemosensitivity in endometrial cancer.
        Oncogene. 2021; 40: 1409-1424
      15. Macut H., Hu X., Tarantino D., Tuning PFKFB3 Bisphosphatase Activity Through Allosteric Interference. Scientific Reports. Published online 2019. doi:10.1038/s41598-019-56708-0

        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA: A Cancer Journal for Clinicians. 2018; (Published online)
        • Tsang J.Y.S.
        • Tse G.M.
        Molecular Classification of Breast Cancer.
        Advances in Anatomic Pathology. 2020; (Published online)
        • Hamilton J.A.
        • Callaghan M.J.
        • Sutherland R.L.
        • Watts C.K.W.
        Identification of PRG1, a novel progestin-responsive gene with sequence homology to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.
        Molecular Endocrinology. 1997; (Published online)
        • Peng F.
        • Li Q.
        • Sun J.Y.
        • Luo Y.
        • Chen M.
        • Bao Y.
        PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis.
        International Journal of Oncology. 2018; (Published online)
        • Abdi S.
        • Montazeri V.
        • Garjani A.
        • Shayanfar A.
        • Pirouzpanah S.
        Coenzyme Q10 in association with metabolism-related AMPK/PFKFB3 and angiogenic VEGF/VEGFR2 genes in breast cancer patients.
        Molecular Biology Reports. 2020; (Published online)
        • La Belle Flynn A.
        • Calhoun B.C.
        • Sharma A.
        • Chang J.C.
        • Almasan A.
        • Schiemann W.P.
        Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression.
        Nature Communications. 2019; (Published online)
      16. Vicent G.P., Ballaré C., Nacht A.S., Induction of Progesterone Target Genes Requires Activation of Erk and Msk Kinases and Phosphorylation of Histone H3. Molecular Cell. Published online 2006. doi:10.1016/j.molcel.2006.10.011

        • Imbert-Fernandez Y.
        • Clem B.F.
        • O'Neal J.
        Estradiol stimulates glucose metabolism via 6-phosphofructo-2-kinase (PFKFB3).
        Journal of Biological Chemistry. 2014; (Published online)
        • Ko B.H.
        • Paik J.Y.
        • Jung K.H.
        Lee KH. 17β-estradiol augments 18F-FDG uptake and glycolysis of T47D breast cancer cells via membrane-initiated rapid PI3K-Akt activation.
        Journal of Nuclear Medicine. 2010; (Published online)
      17. Ahmad D.A.J., Negm O.H., Alabdullah M.L., Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers. Breast Cancer Research and Treatment. Published online 2016. doi:10.1007/s10549-016-3967-9

        • Boscaro C.
        • Carotti M.
        • Albiero M.
        Non-genomic mechanisms in the estrogen regulation of glycolytic protein levels in endothelial cells.
        The FASEB Journal. 2020; 34: 12768-12784
      18. Ge X., Lyu P., Cao Z., Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting. Biochemical and Biophysical Research Communications. Published online 2015. doi:10.1016/j.bbrc.2015.06.068

      19. Gandhi N., Das G. Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications. Cells. Published online 2019. doi:10.3390/cells8020089

        • Castagnoli L.
        • Iorio E.
        • Dugo M.
        Intratumor lactate levels reflect HER2 addiction status in HER2-positive breast cancer.
        Journal of Cellular Physiology. 2019; (Published online)
      20. Madonna M.C., Fox D.B., Crouch B.T., Optical imaging of glucose uptake and mitochondrial membrane potential to characterize HER2 breast tumor metabolic phenotypes. Molecular Cancer Research. Published online 2019. doi:10.1158/1541-7786.MCR-18-0618

        • Shiratori R.
        • Furuichi K.
        • Yamaguchi M.
        Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner.
        Scientific Reports. 2019; (Published online)
      21. Klarer A.C., O'Neal J., Imbert-Fernandez Y., Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism. Cancer and Metabolism. Published online 2014. doi:10.1186/2049-3002-2-2

      22. Lim S.O., Li C.W., Xia W., EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Research. Published online 2016. doi:10.1158/0008-5472.CAN-15-2478

        • Ocaña M.C.
        • Martínez-Poveda B.
        • Quesada A.R.
        • Medina M.Á.
        Glucose favors lipid anabolic metabolism in the invasive breast cancer cell line MDA-MB-231.
        Biology. 2020; (Published online)
      23. Yarden R.I., Papa M.Z. BRCA1 at the crossroad of multiple cellular pathways: Approaches for therapeutic interventions. Molecular Cancer Therapeutics. Published online 2006. doi:10.1158/1535-7163.MCT-05-0471

        • Privat M.
        • Radosevic-Robin N.
        • Aubel C.
        BRCA1 induces major energetic metabolism reprogramming in breast cancer cells.
        PLoS ONE. 2014; (Published online)
      24. Xiang T., Ohashi A., Huang Y., Negative regulation of AKT activation by BRCA1. Cancer Research. Published online 2008. doi:10.1158/0008-5472.CAN-08-3009

      25. Ma J.H., Qin L., Li X. Role of STAT3 signaling pathway in breast cancer. Cell Communication and Signaling. Published online 2020. doi:10.1186/s12964-020-0527-z

      26. Sun X., Wang M., Wang M., Metabolic Reprogramming in Triple-Negative Breast Cancer. Frontiers in Oncology. Published online 2020. doi:10.3389/fonc.2020.00428

        • Madu C.O.
        • Wang S.
        • Madu C.O.
        • Lu Y.
        Angiogenesis in breast cancer progression, diagnosis, and treatment.
        Journal of Cancer. 2020; (Published online)
      27. Sonnenblick A., Venet D., Brohée S., Pondé N., Sotiriou C. pAKT pathway activation is associated with PIK3CA mutations and good prognosis in luminal breast cancer in contrast to p-mTOR pathway activation. npj Breast Cancer. Published online 2019. doi:10.1038/s41523-019-0102-1

      28. Sun M., Paciga J.E., Feldman R.I., Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor α (ERα) via interaction between ERα and PI3K. Cancer Research. Published online 2001.

      29. Paplomata E., O'regan R. The PI3K/AKT/mTOR pathway in breast cancer: Targets, trials and biomarkers. Therapeutic Advances in Medical Oncology. Published online 2014. doi:10.1177/1758834014530023

        • Cairns R.A.
        • Harris I.S.
        • Mak T.W.
        Regulation of cancer cell metabolism.
        Nature Reviews Cancer. 2011; (Published online)
        • Cordero-Espinoza L.
        • Hagen T.
        Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells.
        Journal of Biological Chemistry. 2013; (Published online)
      30. Houddane A., Bultot L., Novellasdemunt L., Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes. Cellular Signalling. Published online 2017. doi:10.1016/j.cellsig.2017.02.019

        • Trefely S.
        • Khoo P.S.
        • Krycer J.R.
        Kinome screen identifies PFKFB3 and glucose metabolism as important regulators of the insulin/insulin-like growth factor (IGF)-1 signaling pathway.
        Journal of Biological Chemistry. 2015; (Published online)
      31. Almacellas E., Pelletier J., Manzano A., Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1. iScience. Published online 2019. doi:10.1016/j.isci.2019.09.040

      32. Magaway C., Kim E., Jacinto E. Targeting mTOR and Metabolism in Cancer: Lessons and Innovations. Cells. Published online 2019. doi:10.3390/cells8121584

      33. Bazzichetto C., Conciatori F., Pallocca M., Pten as a prognostic/predictive biomarker in cancer: An unfulfilled promise? Cancers. Published online 2019. doi:10.3390/cancers11040435

        • Khabaz M.N.
        • Al-Sakkaf K.
        • Qureshi I.A.
        Expression of p-AMPK is associated with hormone receptor phenotypes and lymph node metastasis in breast cancer.
        International Journal of Clinical and Experimental Pathology. 2017; (Published online)
      34. Yi Y., Chen D., Ao J., Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation. Proceedings of the National Academy of Sciences of the United States of America. Published online 2020. doi:10.1073/pnas.1914786117

        • Mendoza E.E.
        • Pocceschi M.G.
        • Kong X.
        Control of glycolytic flux by AMP-activated protein kinase in tumor cells adapted to low ph1.
        Translational Oncology. 2012; (Published online)
      35. Clem B., Telang S., Clem A., Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Molecular Cancer Therapeutics. Published online 2008. doi:10.1158/1535-7163.MCT-07-0482

      36. Chen L., Mayer J.A., Krisko T.I., Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Research. Published online 2009. doi:10.1158/0008-5472.CAN-09-1636

      37. Ge X., Lyu P., Gu Y., Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation. Biochemical and Biophysical Research Communications. Published online 2015. doi:10.1016/j.bbrc.2015.07.052

        • Niyaz M.
        • Khan M.S.
        • Mudassar S.
        Hedgehog Signaling: An Achilles’ Heel in Cancer.
        Translational Oncology. 2019; (Published online)
        • Sarkar D.K.
        • Jana D.
        • Patil P.S.
        Role of NF-κB as a Prognostic Marker in Breast Cancer: A Pilot Study in Indian Patients.
        Indian Journal of Surgical Oncology. 2013; (Published online)
      38. Cantelmo A.R., Conradi L.C., Brajic A., Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell. Published online 2016. doi:10.1016/j.ccell.2016.10.006

      39. Reid M.A., Lowman X.H., Pan M., IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes and Development. Published online 2016. doi:10.1101/gad.287235.116

        • Chen D.P.
        • Ning W.R.
        • Jiang Z.Z.
        Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.
        Journal of Hepatology. 2019; (Published online)
        • Chesney J.A.
        • Telang S.
        • Yaddanapudi K.
        • Grewal J.S.
        Targeting 6-phosphofructo-2-kinase (PFKFB3) as an immunotherapeutic strategy.
        Journal of Clinical Oncology. 2016; (Published online)
        • Gasco M.
        • Shami S.
        • Crook T.
        The p53 pathway in breast cancer.
        Breast Cancer Research. 2002; (Published online)
        • Bertheau P.
        • Lehmann-Che J.
        • Varna M.
        P53 in breast cancer subtypes and new insights into response to chemotherapy.
        Breast. 2013; (Published online)
        • Liu J.
        • Zhang C.
        • Hu W.
        • Feng Z.
        Tumor suppressor p53 and metabolism.
        Journal of Molecular Cell Biology. 2019; (Published online)
        • Franklin D.A.
        • He Y.
        • Leslie P.L.
        P53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway.
        Scientific Reports. 2016; (Published online)
        • Liu J.
        • Liu Z.X.
        • Wu Q.N.
        Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming.
        Nature Communications. 2020; (Published online)