Regulation of cancer stem cells in triple negative breast cancer

Abstract

Triple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the successes of emerging targeted therapies, relapse, recurrence, and therapy failure rates in TNBC significantly outpace other subtypes of breast cancer. Mounting evidence suggests accumulation of therapy resistant Cancer Stem Cell (CSC) populations within TNBCs contributes to poor clinical outcomes. These CSCs are enriched in TNBC compared to non-TNBC breast cancers. The mechanisms underlying CSC accumulation have been well-characterized and discussed in other reviews. In this review, we focus on TNBC-specific mechanisms that allow the expansion and activity of self-renewing CSCs. We highlight cellular signaling pathways and transcription factors, specifically enriched in TNBC over non-TNBC breast cancer, contributing to stemness. We also analyze publicly available single-cell RNA-seq data from basal breast cancer tumors to highlight the potential of emerging bioinformatic approaches in identifying novel drivers of stemness in TNBC and other cancers.

Keywords

Cancer stem cells / TNBC / transcriptional regulation / breast cancer

References

[1] DeSantis CE,Gaudet MM.Breast cancer statistics, 2019..CA Cancer J Clin2019;69:438-51

[2] Carey LA,Livasy CA.Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study..JAMA2006;295:2492-502

[3] Foulkes WD,Reis-Filho JS.Triple-negative breast cancer..N Engl J Med2010;363:1938-48

[4] Burstein MD,Poage GM.Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer..Clin Cancer Res2015;21:1688-98 PMCID:PMC4362882

[5] Boyle P.Triple-negative breast cancer: epidemiological considerations and recommendations..Ann Oncol2012;23:vi7-12

[6] Griffiths CL.Triple negative breast cancer: a brief review of its characteristics and treatment options..J Pharm Pract2012;25:319-23

[7] Ballinger T,Miller K.Triple negative breast cancer-review of current and emerging therapeutic strategies..2016;12:89

[8] Ma F,Wang H.Enriched CD44⁺/CD24^-population drives the aggressive phenotypes presented in triple-negative breast cancer (TNBC)..Cancer Lett2014;353:153-9

[9] Li H,Wang H.Stem cell marker aldehyde dehydrogenase 1 (ALDH1)-expressing cells are enriched in triple-negative breast cancer..Int J Biol Markers2013;28:357-64

[10] Honeth G,Ringnér M.The CD44⁺/CD24^-phenotype is enriched in basal-like breast tumors..Breast Cancer Res2008;10:R53 PMCID:PMC2481503

[11] Talukdar S,Emdad L,Sarkar D.Dormancy and cancer stem cells: An enigma for cancer therapeutic targeting..Adv Cancer Res2019;141:43-84

[12] Wicha MS,Dontu G.Cancer stem cells: an old idea-a paradigm shift..Cancer Res2006;66:1883-90

[13] De Sousa e Melo F.Wnt signaling in cancer stem cell biology..Cancers2016;8:60 PMCID:PMC4963802

[14] Braune E-B,Lendahl U.Notch and Wnt dysregulation and its relevance for breast cancer and tumor initiation..Biomedicines2018;6:101 PMCID:PMC6315509

[15] Bhardwaj G,Wu D.Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation..Nat Immunol2001;2:172-80

[16] Aponte PM.Stemness in cancer: stem cells, cancer stem cells, and their microenvironment..Stem Cells Int2017;2017:5619472 PMCID:PMC5394399

[17] Serman L,Serman A.Epigenetic alterations of the Wnt signaling pathway in cancer: a mini review..Bosn J Basic Med Sci2014;14:191 PMCID:PMC4333971

[18] Toh TB,Chow EK-H.Epigenetics in cancer stem cells..Mol Cancer2017;16:29 PMCID:PMC5286794

[19] Ricardo S,Gerhard R.Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype..J Clin Pathol2011;64:937-46

[20] Lee K-L,Ho Y-S.Triple-negative breast cancer: Current understanding and future therapeutic breakthrough targeting cancer stemness..Cancers2019;11:1334 PMCID:PMC6769912

[21] Liedtke C,Hess KR.Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer..J Clin Oncol Off J Am Soc Clin Oncol2008;26:1275-81

[22] Petrelli F,Borgonovo K.The value of platinum agents as neoadjuvant chemotherapy in triple-negative breast cancers: a systematic review and meta-analysis..Breast Cancer Res Treat2014;144:223-32

[23] Park S-Y,Nam J-S.Targeting Cancer Stem Cells in Triple-Negative Breast Cancer..Cancers2019;11:965 PMCID:PMC6678244

[24] Qin J-J,Zhang J.STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review..J Exp Clin Cancer Res CR2019;38:195 PMCID:PMC6518732

[25] Zhang F,Deng Q.UCP1 regulates ALDH-positive breast cancer stem cells through releasing the suppression of Snail on FBP1..Cell Biol Toxicol2020;

[26] Chaffer CL,Lee T.Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity..Cell2013;154:61-74 PMCID:PMC4015106

[27] Vesuna F,Kimble B.Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression..Neoplasia N Y NY2009;11:1318 PMCID:PMC2794513

[28] Zhang J-M,Jiang M.OCT4 but not SOX2 expression correlates with worse prognosis in surgical patients with triple-negative breast cancer..Breast Cancer2018;25:447-55

[29] Lee K,Balko JM.MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation..Cell Metab2017;26:633-47.e7 PMCID:PMC5650077

[30] Samanta D,Chaturvedi P,Semenza GL.Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells..Proc Natl Acad Sci2014;111:E5429-38 PMCID:PMC4273385

[31] Fultang N.Pandey MK.Wnt Signaling in Breast Cancer Oncogenesis, Development and Progression..Advances in Cancer Signal Transduction and Therapy.2020;Bentham Science Publishes1-28

[32] Pohl S-G,Agostino M,Kumar AP.Wnt signaling in triple-negative breast cancer..Oncogenesis2017;6:e310 PMCID:PMC5520491

[33] Zhang S,Cui B.ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth..PLoS One2012;7:e31127 PMCID:PMC3293865

[34] Bilir B,Moreno CS.Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells..J Transl Med2013;11:280 PMCID:PMC4228255

[35] Xu J,Choudhury N,Goss KH.β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells..PLoS One2015;10:e0117097 PMCID:PMC4319896

[36] Jang G-B,Cho S-D.Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype..Sci Rep2015;5:12465 PMCID:PMC5378883

[37] Giancotti FG.Mechanisms governing metastatic dormancy and reactivation..Cell2013;155:750-64 PMCID:PMC4354734

[38] DiMeo TA,Phadke P.A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer..Cancer Res2009;69:5364-73 PMCID:PMC2782448

[39] Debeb BG,Xu W.Histone Deacetylase Inhibitors Stimulate Dedifferentiation of Human Breast Cancer Cells Through WNT/β-Catenin Signaling..Stem Cells2012;30:2366-77 PMCID:PMC4545658

[40] Lin C-C,Moody R.Targeting LRP8 inhibits breast cancer stem cells in triple-negative breast cancer..Cancer Lett2018;438:165-73 PMCID:PMC6945120

[41] Henry C,Hawkins NJ.Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both β-catenin dependent and independent Wnt signalling..J Cancer Res Clin Oncol2015;141:243-54

[42] Karvonen H,Kaleva L,Ungureanu D.Molecular mechanisms associated with ROR1-mediated drug resistance: crosstalk with Hippo-YAP/TAZ and BMI-1 pathways..Cells2019;8:812 PMCID:PMC6721603

[43] Chen J-F,Xiang L-S.EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling..Oncotarget2016;7:41540-58 PMCID:PMC5173077

[44] Zhang K,Wang X.WNT/β-catenin directs self-renewal symmetric cell division of hTERThigh prostate cancer stem cells..Cancer Res2017;77:2534-47

[45] Ji C,Yi W.Capillary morphogenesis gene 2 maintains gastric cancer stem-like cell phenotype by activating a Wnt/β-catenin pathway..Oncogene2018;37:3953-66 PMCID:PMC6053357

[46] Wang T,Liu S.SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance..Cancer Lett2018;430:11-24

[47] Ibrahim SA,Vilardo L.Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling..PLoS One2013;8:e85737 PMCID:PMC3877388

[48] Kolev VN,Wright QG.Inhibition of FAK kinase activity preferentially targets cancer stem cells..Oncotarget2017;8:51733-47 PMCID:PMC5584283

[49] Cleary AS,Gestl SA.Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers..Nature2014;508:113-7 PMCID:PMC4050741

[50] Schroeter EH,Kopan R.Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain..Nature1998;393:382-6

[51] Kovall RA.More complicated than it looks: assembly of Notch pathway transcription complexes..Oncogene2008;27:5099-109

[52] Giuli MV,Screpanti I,Checquolo S.Notch signaling activation as a hallmark for triple-negative breast cancer subtype..J Oncol2019;2019:8707053 PMCID:PMC6657611

[53] Stylianou S,Brennan K.Aberrant activation of notch signaling in human breast cancer..Cancer Res2006;66:1517-25

[54] Harrison H,Howell SJ.Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor..Cancer Res2010;70:709-18 PMCID:PMC3442245

[55] Speiser J,Drinka E.Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer..Int J Surg Pathol2012;20:139-45

[56] Yu F,Chen H.Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion..Oncogene2011;30:2161-72 PMCID:PMC3088782

[57] Choi S,Park A.BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling..Sci Rep2019;9:11724 PMCID:PMC6692307

[58] Bernardi R.Hallmarks of triple negative breast cancer emerging at last?.Cell Res2014;24:904-5 PMCID:PMC4123289

[59] Xing F,Watabe M.Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells..Oncogene2011;30:4075-86 PMCID:PMC3145824

[60] Zhang J,Sun H.NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling..Oncotarget2016;7:61036-53 PMCID:PMC5308634

[61] Takada M,Inuzuka H.EglN2 contributes to triple negative breast tumorigenesis by functioning as a substrate for the FBW7 tumor suppressor..Oncotarget2017;8:6787-95 PMCID:PMC5351669

[62] Meyer AE,Stelloh C,Rao S.Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation..Neoplasia2020;22:644-58 PMCID:PMC7573506

[63] Liubomirski Y,Meshel T.Notch-mediated tumor-stroma-inflammation networks promote invasive properties and CXCL8 expression in triple-negative breast cancer..Front Immunol2019;10:804 PMCID:PMC6492532

[64] Merchant AA.Targeting Hedgehog-a cancer stem cell pathway..Clin Cancer Res2010;16:3130-40 PMCID:PMC2888641

[65] Skoda AM,Karin V,Vranic S.The role of the Hedgehog signaling pathway in cancer: A comprehensive review..Bosn J Basic Med Sci2018;18:8-20 PMCID:PMC5826678

[66] Habib JG.The hedgehog pathway in triple-negative breast cancer..Cancer Med2016;5:2989-3006 PMCID:PMC5083752

[67] O’Toole SA,Shearer RF.Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer..Cancer Res2011;71:4002-14

[68] Han B,Jin Y.FOXC1 activates smoothened-independent hedgehog signaling in basal-like breast cancer..Cell Rep2015;13:1046-58 PMCID:PMC4806384

[69] Tao Y,Zhang Q.Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer..Oncol Lett2011;2:995-1001 PMCID:PMC3408022

[70] Chen B,Tang W.Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer..Nat Chem Biol2009;5:100-7 PMCID:PMC2628455

[71] Reyes-Ramos AM,Rodríguez-Merced NJ.Mesenchymal Cells Support the Oncogenicity and Therapeutic Response of the Hedgehog Pathway in Triple-Negative Breast Cancer..Cancers2019;11:1522 PMCID:PMC6826628

[72] Guerrini G,Filippi I.Carbonic anhydrase XII expression is linked to suppression of Sonic hedgehog ligand expression in triple negative breast cancer cells..Biochem Biophys Res Commun2019;516:408-13

[73] Nagata T,Sekine S.KLF4 and NANOG are prognostic biomarkers for triple-negative breast cancer..Breast Cancer2017;24:326-35

[74] Li Q,Chung H.The pluripotency factor NANOG binds to GLI proteins and represses hedgehog-mediated transcription..J Biol Chem2016;291:7171-82 PMCID:PMC4807297

[75] Durand N,Storz P.Protein Kinase D Enzymes as Regulators of EMT and Cancer Cell Invasion..J Clin Med2016;5:20 PMCID:PMC4773776

[76] Durand N,Storz P.Functional and therapeutic significance of protein kinase D enzymes in invasive breast cancer..Cell Mol Life Sci2015;72:4369-82 PMCID:PMC4618102

[77] Alpsoy A.Protein kinase D2 silencing reduced motility of doxorubicin-resistant MCF7 cells..Tumor Biol2015;36:4417-26

[78] Borges S,Perez EA.Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis..Breast Cancer Res2013;15:R66 PMCID:PMC4052945

[79] Hao Q,Gan H.Protein Kinases D2 and D3 Are Novel Growth Regulators in HCC1806 Triple-negative Breast Cancer Cells..Anticancer Res2013;33:393-99

[80] Lieb WS,Tamas R.The GEF-H1/PKD3 signaling pathway promotes the maintenance of triple-negative breast cancer stem cells..Int J Cancer2020;146:3423-34

[81] Huck B,Hausser A.Elevated protein kinase D3 (PKD3) expression supports proliferation of triple-negative breast cancer cells and contributes to mTORC1-S6K1 pathway activation..J Biol Chem2014;289:3138-47 PMCID:PMC3916519

[82] Huck B,Franz-Wachtel M,Hausser A.GIT1 phosphorylation on serine 46 by PKD3 regulates paxillin trafficking and cellular protrusive activity..J Biol Chem2012;287:34604-13 PMCID:PMC3464566

[83] Harrison DA.The Jak/STAT pathway..Cold Spring Harb Perspect Biol2012;4:a011205 PMCID:PMC3282412

[84] Ghoreschi K,O’Shea JJ.Janus kinases in immune cell signaling..Immunol Rev2009;228:273-87 PMCID:PMC2782696

[85] Tang Y.JAK-STAT3 and somatic cell reprogramming..JAKSTAT2013;2:e24935 PMCID:PMC3894236

[86] Boudny V.JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription..Neoplasma2002;49:349-55

[87] Kim S-Y,Song X.Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells..Cell Signal2013;25:961-9 PMCID:PMC3595341

[88] Marotta LL,Marusyk A.The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24^- stem cell-like breast cancer cells in human tumors..J Clin Invest2011;121:2723-35 PMCID:PMC3223826

[89] Ginestier C,Diebel ME.CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts..J Clin Invest2010;120:485-97 PMCID:PMC2810075

[90] Hartman ZC,Den Hollander P.Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8..Cancer Res2013;73:3470-80 PMCID:PMC3853111

[91] Thiagarajan PS,Bhagrath M.STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance..Endocr Relat Cancer2017;24:415-26 PMCID:PMC5551450

[92] Liu Y,Sheng J.HN1L promotes triple-negative breast cancer stem cells through LEPR-STAT3 pathway..Stem Cell Rep2018;10:212-27 PMCID:PMC5768915

[93] Barbie TU,Aref AR.Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth..J Clin Invest2014;124:5411-23 PMCID:PMC4348940

[94] Doherty MR,Junk DJ.Interferon-beta represses cancer stem cell properties in triple-negative breast cancer..Proc Natl Acad Sci2017;114:13792-7 PMCID:PMC5748193

[95] Qadir AS,Brockway S.CD95/Fas increases stemness in cancer cells by inducing a STAT1-dependent type I interferon response..Cell Rep2017;18:2373-86 PMCID:PMC5474321

[96] Verrecchia F.TGF-beta and TNF-alpha: antagonistic cytokines controlling type I collagen gene expression..Cell Signal2004;16:873-80

[97] Dash S,Srivastava A,Mukherjee S.Exploring the extensive crosstalk between the antagonistic cytokines- TGF-β and TNF-α in regulating cancer pathogenesis..Cytokine2020;155348:

[98] Moses H.TGF-β biology in mammary development and breast cancer..Cold Spring Harb Perspect Biol2011;3:a003277 PMCID:PMC3003461

[99] Zarzynska JM.Two faces of TGF-beta1 in breast cancer..Mediators Inflamm2014;2014:141747 PMCID:PMC4033515

[100] Lamouille S,Derynck R.Molecular mechanisms of epithelial-mesenchymal transition..Nat Rev Mol Cell Biol2014;15:178-96 PMCID:PMC4240281

[101] Moustakas A.Induction of epithelial-mesenchymal transition by transforming growth factor β..Seminars in cancer biology2012;22:446-54

[102] Derynck R,Saeteurn KY.Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition..Curr Opin Cell Biol2014;31:56-66 PMCID:PMC4657734

[103] Gonzalez DM.Signaling mechanisms of the epithelial-mesenchymal transition..Sci Signal2014;7:re8 PMCID:PMC4372086

[104] Shipitsin M,Argani P.Molecular definition of breast tumor heterogeneity..Cancer Cell2007;11:259-73

[105] Bhola NE,Dugger TC.TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer..J Clin Invest2013;123:1348-58 PMCID:PMC3582135

[106] Serra R,Jiang W.Wnt5a as an effector of TGFβ in mammary development and cancer..J Mammary Gland Biol Neoplasia2011;16:157-67 PMCID:PMC3107509

[107] Bierie B,Abel TW.Transforming growth factor-β regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment..Cancer Res2008;68:1809-19

[108] Lindau D,Kroesen M,Adema GJ.The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells..Immunology2013;138:105-15 PMCID:PMC3575763

[109] Cabrera MC,Hurt EM.Cancer stem cell plasticity and tumor hierarchy..World J Stem Cells2015;7:27-36 PMCID:PMC4300934

[110] Balkwill F.Tumour necrosis factor and cancer..Nat Rev Cancer2009;9:361-71

[111] Liu W,Shi P.TNF-α increases breast cancer stem-like cells through up-regulating tAZ expression via the non-canonical nf-κB pathway..Sci Rep2020;10:1804 PMCID:PMC7000832

[112] Storci G,Mari S.TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype..J Cell Physiol2010;225:682-91 PMCID:PMC2939957

[113] Li C-W,Huo L.Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1..Cancer Res2012;72:1290-300 PMCID:PMC3350107

[114] Fresno JV,Cejas P,González-Barón M.PI3K/Akt signalling pathway and cancer..Cancer Treat Rev2004;30:193-204

[115] Bai J,Zhang X-Y.HIF-2α regulates CD44 to promote cancer stem cell activation in triple-negative breast cancer via PI3K/AKT/mTOR signaling..World J Stem Cells2020;12:87-99 PMCID:PMC7031759

[116] Rivas S,Antón IM.Role of Akt Isoforms Controlling Cancer Stem Cell Survival, Phenotype and Self-Renewal..Biomedicines2018;6:29 PMCID:PMC5874686

[117] Abraham AG.PI3K/Akt-mediated regulation of p53 in cancer..Biochem Soc Trans2014;42:798-803

[118] Pascual J.Targeting the PI3-kinase pathway in triple-negative breast cancer..Ann Oncol Off J Eur Soc Med Oncol2019;30:1051-60

[119] Martínez-Revollar G,Martin-Tapia D.Heterogeneity between triple negative breast cancer cells due to differential activation of Wnt and PI3K/AKT pathways..Exp Cell Res2015;339:67-80

[120] Sulaiman A,Lam KM.Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells..Cell Death Dis2018;9:815 PMCID:PMC6062597

[121] Tian J,Dai M.Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells..Br J Cancer2018;119:1495-507 PMCID:PMC6288167

[122] Britschgi A,Brinkhaus H.JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer..Cancer Cell2012;22:796-811

[123] Brabletz T,Nieto MA.EMT in cancer..Nat Rev Cancer2018;18:128-34

[124] Jiralerspong S,Palla SL,Hung M,Gonzalez-Angulo M.Correlation of Snail expression and survival in patients with early-stage triple-negative breast cancer (TNBC)..J Clin Oncol2010;28:10525

[125] Hwang W-L,Tsai M-L.SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells..Gastroenterology2011;141:279-91291.e1-5

[126] Dong C,Wu Y.Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer..Cancer Cell2013;23:316-31 PMCID:PMC3703516

[127] Lu L,Lin X.Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail..Cell Death Differ2020;27:255-68 PMCID:PMC7205888

[128] Feldker N,Schuhwerk H.Genome-wide cooperation of EMT transcription factor ZEB 1 with YAP and AP-1 in breast cancer..EMBO J2020;39:e103209 PMCID:PMC7459422

[129] He Y,Pan W,Liang L.Interleukin-31 Receptor α Is Required for Basal-Like Breast Cancer Progression..Front Oncol2020;10:816 PMCID:PMC7266966

[130] Shi J,Zeng L.Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer..Cancer Cell2014;25:210-25 PMCID:PMC4004960

[131] He J,Saha S,Guo H.Inhibition of USP2 eliminates cancer stem cells and enhances TNBC responsiveness to chemotherapy..Cell Death Dis2019;10:285 PMCID:PMC6437220

[132] Bao B,Ali S.The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness..Biochim Biophys Acta2012;1826:272-96 PMCID:PMC3788359

[133] Lu H,Xiang L.Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype..Proc Natl Acad Sci2015;112:E4600-9 PMCID:PMC4547233

[134] Chaturvedi P,Takano N.Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment..Proc Natl Acad Sci2014;111:E2120-9 PMCID:PMC4034192

[135] Zhang H,Xiang L.HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells..Proc Natl Acad Sci2015;112:E6215-23 PMCID:PMC4653179

[136] Lan J,Samanta D,Lu Y.Hypoxia-inducible factor 1-dependent expression of adenosine receptor 2B promotes breast cancer stem cell enrichment..Proc Natl Acad Sci2018;115:E9640-8 PMCID:PMC6187157

[137] Xiang L,Hu H.Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype..Oncotarget2014;5:12509-27 PMCID:PMC4350363

[138] Zandberga E,Ābols A,Trapencieris P.Depletion of carbonic anhydrase IX abrogates hypoxia-induced overexpression of stanniocalcin-1 in triple negative breast cancer cells..Cancer Biol Ther2017;18:596-605 PMCID:PMC5653187

[139] Lock FE,Lou Y.Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche..Oncogene2013;32:5210-9

[140] Sarnella A,Hill BS.A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity..Int J Mol Sci2020;21:8405 PMCID:PMC7664880

[141] Liu A,Liu S.Pluripotency transcription factors and cancer stem cells: small genes make a big difference..Chin J Cancer2013;32:483-7 PMCID:PMC3845564

[142] Li Y,Lan F.Generation of human-induced pluripotent stem cells from gut mesentery-derived cells by ectopic expression of OCT4/SOX2/NANOG..Cell Reprogramming2010;12:237-47

[143] Nichols J,Anastassiadis K.Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4..Cell1998;95:379-91

[144] Wang Y-J.The emerging roles of Oct4 in tumor-initiating cells..Am J Physiol-Cell Physiol2015;309:C709-18 PMCID:PMC4725440

[145] Cheng C-C,Wang X-J.Stat3/Oct-4/c-Myc signal circuit for regulating stemness-mediated doxorubicin resistance of triple-negative breast cancer cells and inhibitory effects of WP1066..Int J Oncol2018;53:339-48

[146] Jin X,Qu H,Wang X.OCT4 Suppresses Metastasis in Breast Cancer Cells Through Activation of STAT3 Signaling..Research Square2020;

[147] Yao GD,Chen KX.SOX2 gene expression and its role in triple negative breast cancer tissues..J Biol Regul Homeost Agents2018;32:1399-406

[148] Liu P,Song C.SOX2 promotes cell proliferation and metastasis in triple negative breast cancer..Front Pharmacol2018;9:942 PMCID:PMC6110877

[149] Mukherjee P,Chattopadhyay D.Modulation of SOX2 expression delineates an end-point for paclitaxel-effectiveness in breast cancer stem cells..Sci Rep2017;7:1-16 PMCID:PMC5569040

[150] Jung K,Wang P.Triple negative breast cancers comprise a highly tumorigenic cell subpopulation detectable by its high responsiveness to a sex determining region Y box 2 (Sox2) regulatory region 2 (SRR2) reporter..Oncotarget2015;6:10366

[151] Samanta S,Goel HL.IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG..Oncogene2016;35:1111-21 PMCID:PMC5784260

[152] Zhao D,Sun J.VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2..Oncogene2015;34:3107-19

[153] Zhang Y,Qiao X.LIPH promotes metastasis by enriching stem-like cells in triple-negative breast cancer..J Cell Mol Med2020;24:9125-34 PMCID:PMC7417731

[154] Schwarz BA,Silva JC.Nanog is Dispensable for the Generation of Induced Pluripotent Stem Cells..Curr Biol CB2014;24:347-50 PMCID:PMC4007021

[155] Thiagarajan PS,Turaga SM.Cx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase..Nat Commun2018;9:1-14 PMCID:PMC5805730

[156] Nagata T,Sekine S.Prognostic significance of NANOG and KLF4 for breast cancer..Breast Cancer2014;21:96-101

[157] Qi X,Ma S.p38γ MAPK is a therapeutic target for triple-negative breast cancer by stimulation of cancer stem-like cell expansion..Stem Cells2015;33:2738-47 PMCID:PMC4792188

[158] Rowland BD,Peeper DS.The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene..Nat Cell Biol2005;7:1074-82

[159] Nagata T,Long XL.KLF4 Improve Prognosis of Triple-negative Breast Cancer by Suppression of Epithelial-mesenchymal Transition..Breast Can Curr Res2016;01:

[160] Zhou Z,Hu D.A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy..EBioMedicine2019;44:98-111 PMCID:PMC6604046

[161] Sharma SB.Kruppel-like factor 4 (KLF4) regulates protumorigenic signaling in triple-negative breast cancer (TNBC) cells. Graduate Theses, Dissertations, and Problem Reports2015;

[162] Dang CV.MYC on the Path to Cancer..Cell2012;149:22-35 PMCID:PMC3345192

[163] Yang A,Schulte BA,Tew KD.MYC inhibition depletes cancer stem-like cells in triple-negative breast cancer..Cancer Res2017;77:6641-50 PMCID:PMC5712265

[164] Yin S,Xu L,Reddy KB.Myc mediates cancer stem-like cells and EMT changes in triple negative breast cancers cells..PLoS One2017;12:e0183578 PMCID:PMC5560738

[165] Lee Y-C,Chen Y-Y.Hsp90α mediates BMI1 expression in breast cancer stem/progenitor cells through facilitating nuclear translocation of c-Myc and EZH2..Int J Mol Sci2017;18:1986 PMCID:PMC5618635

[166] Teo WS,Karthikeyan N.Id proteins promote a cancer stem cell phenotype in triple negative breast cancer via Robo1-dependent c-Myc activation..bioRxiv2019;497313

[167] Ito Y,Chuang LSH.The RUNX family: developmental regulators in cancer..Nat Rev Cancer2015;15:81-95

[168] Ferrari N.Investigating RUNX transcription factors in mammary gland development and breast cancer.2013;

[169] Fritz AJ,Boyd J.RUNX transcription factor mediated control of breast cancer stem cells..J Cell Physiol2020;235:7261-72 PMCID:PMC7415511

[170] Ferrari N,Nixon C.Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer..PLoS One2014;9:e100759 PMCID:PMC4072705

[171] Ran R,Ariffin NS.RUNX/CBFβ transcription factor complexes promote the phenotypic plasticity of metastatic breast cancer cells..bioRxiv2019;562538

[172] Felcher CM,Sola MEG,Kordon EC. Inhibition of RUNX-CBFβ binding reduces RSPO3 expression and EMT features in breast cancer cells. AACR Annual Meeting 2020 Philadelphia, PA

[173] Passaniti A,Qiao Y,Finch-Edmondson M.Groner Y,Liu P,Speck NA.Roles of RUNX in Hippo pathway signaling..RUNX Proteins in Development and Cancer.2017;SingaporeSpringer435-48

[174] Piccolo S,Cordenonsi M.The biology of YAP/TAZ: hippo signaling and beyond..Physiol Rev2014;94:1287-312

[175] Yimlamai D,Galli GG.Hippo pathway activity influences liver cell fate..Cell2014;157:1324-38 PMCID:PMC4136468

[176] Cordenonsi M,Azzolin L.The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells..Cell2011;147:759-72

[177] Kim T,Hwang D.A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness..Nat Commun2015;6:10186 PMCID:PMC4703869

[178] Guo L,Zhang J,Shao G.Knockdown of TAZ modifies triple-negative breast cancer cell sensitivity to EGFR inhibitors by regulating YAP expression..Oncol Rep2016;36:729-36

[179] Sorrentino G,Zannini A.Glucocorticoid receptor signalling activates YAP in breast cancer..Nat Commun2017;8:14073 PMCID:PMC5253666

[180] Knight JF,Kuzmin E.KIBRA (WWC1) Is a metastasis suppressor gene affected by chromosome 5q loss in triple-negative breast cancer..Cell Rep2018;22:3191-205 PMCID:PMC5873529

[181] Mussell A,Chen Y.USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer..Cancers2020;12:3090 PMCID:PMC7690829

[182] Taniguchi K.NF-κB, inflammation, immunity and cancer: coming of age..Nat Rev Immunol2018;18:309-24

[183] Yamamoto M,Ito-Kureha T,Yamaguchi N.NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype..Nat Commun2013;4:2299

[184] Hossain F,Ucar DA.Notch signaling regulates mitochondrial metabolism and NF-κB activity in triple-negative breast cancer cells via IKKα-dependent non-canonical pathways..Front Oncol2018;8:575 PMCID:PMC6289043

[185] Orlova Z,Castro-Oropeza R.IKKε regulates the breast cancer stem cell phenotype..Biochim Biophys Acta BBA-Mol Cell Res2019;1866:598-611

[186] Patel AP,Trombetta JJ.Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma..Science2014;344:1396-401 PMCID:PMC4123637

[187] Horning AM,Lin C-K.Single-Cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell-Cycle-Related transcription and attenuated androgen response..Cancer Res2018;78:853-64 PMCID:PMC5983359

[188] Zhao Y,Natarajan S.Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells..BMC Med Genomics2019;12:79 PMCID:PMC6545015

[189] Yeo SK,Okamoto T.Single-cell RNA-sequencing reveals distinct patterns of cell state heterogeneity in mouse models of breast cancer..Elife2020;9:e58810 PMCID:PMC7447441

[190] Butler A,Smibert P,Satija R.Integrating single-cell transcriptomic data across different conditions, technologies, and species..Nat Biotechnol2018;36:411-20 PMCID:PMC6700744

[191] Ren D,Kong R.Targeting brain-adaptive cancer stem cells prohibits brain metastatic colonization of triple-negative breast cancer..Cancer Res2018;78:2052-64 PMCID:PMC5899649

[192] da Silveira WA,Sicchieri RD.Transcription Factor Networks derived from Breast Cancer Stem Cells control the immune response in the Basal subtype..Sci Rep2017;7:2851 PMCID:PMC5460106

[193] Chen K-HE,Lopez T.Use of a novel camelid-inspired human antibody demonstrates the importance of MMP-14 to cancer stem cell function in the metastatic process..Oncotarget2018;9:29431-44 PMCID:PMC6047671

[194] Kulesza DW,Kaminska B.Knockdown of STAT3 targets a subpopulation of invasive melanoma stem-like cells..Cell Biol Int2019;43:613-22

[195] Oktem G,Guven U.Cancer stem cell differentiation: TGFβ1 and versican may trigger molecules for the organization of tumor spheroids..Oncol Rep2014;32:641-9

[196] Chen Z,Yao L,Gao Y.The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1..J Biol Chem2018;293:7982-92 PMCID:PMC5971456

[197] Man J,Huang H.Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells..Cell Stem Cell2018;22:104-18.e6 PMCID:PMC5756127

[198] Huang D,Tian J.Udp-glucose dehydrogenase as a novel field-specific candidate biomarker of prostate cancer..Int J Cancer2010;126:315-27 PMCID:PMC2794918

[199] Temian DC,Irimie AI.The Epigenetics of Triple-Negative and Basal-Like Breast Cancer: Current Knowledge..J Breast Cancer2018;21:233-43 PMCID:PMC6158152

[200] Li G,Ma W.Transcriptomic and epigenetic analysis of breast cancer stem cells..Epigenomics2018;10:765-83

[201] Kagara N,Kuo C.Epigenetic regulation of cancer stem cell genes in triple-negative breast cancer..Am J Pathol2012;181:257-67

[202] Schech A,Yu S,Sabnis G.Histone deacetylase inhibitor entinostat inhibits tumor-initiating cells in triple-negative breast cancer cells..Mol Cancer Ther2015;14:1848-57

[203] Stirzaker C,Song JZ.Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value..Nat Commun2015;6:5899

[204] Nakai K,Liao H-W,Hung M-C.The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells..Breast Cancer2018;25:74-80

[205] Xiong Z,Yang L.Decitabine Reverses CSC-Induced Docetaxel Resistance via Epigenetic Regulation of DAB2IP in TNBC..Research Saquare2020;

[206] Bao B,Mitrea C,Dyson G.Role of TET1 and 5hmC in an Obesity-Linked Pathway Driving Cancer Stem Cells in Triple-Negative Breast Cancer..Mol Cancer Res2020;18:1803-14 PMCID:PMC7718329

[207] Jones PA.The epigenomics of cancer..Cell2007;128:683-92 PMCID:PMC3894624

[208] Yomtoubian S,Verma A.Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer..Cell Rep2020;30:755-70.e6

[209] Witt AE,Lee TI.Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer..Oncogene2017;36:1707-20 PMCID:PMC5364039

[210] Caslini C,Ban YJ,Ince TA.HDAC7 regulates histone 3 lysine 27 acetylation and transcriptional activity at super-enhancer-associated genes in breast cancer stem cells..Oncogene2019;38:6599-614

[211] Su Y,Nguyen TD,Santucci-Pereira J.Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors..J Exp Clin Cancer Res2018;37:314 PMCID:PMC6295063

[212] Darvin P,Elkord E.PD-L1 Expression in Human Breast Cancer Stem Cells Is Epigenetically Regulated through Posttranslational Histone Modifications..J Oncol2019;2019:e3958908 PMCID:PMC6409026

[213] Torres CM,Burney MJ.The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity..Science2016;353:aaf1644 PMCID:PMC5131846

[214] Li X,Bleilevens A,Maurer J.Chemotherapeutic Stress Influences Epithelial-Mesenchymal Transition and Stemness in Cancer Stem Cells of Triple-Negative Breast Cancer..Int J Mol Sci2020;21:404 PMCID:PMC7014166

[215] Huang QD,Cai YJ.IMP3 promotes TNBC stem cell property through miRNA-34a regulation..Eur Rev Med Pharmacol Sci2018;22:2688-96

[216] Sun X,Zheng M,Zheng W.MicroRNA-223 Increases the Sensitivity of Triple-Negative Breast Cancer Stem Cells to TRAIL-Induced Apoptosis by Targeting HAX-1..PLoS One2016;11:e0162754 PMCID:PMC5019415

[217] DeCastro AJ,Hutchinson J,Cherukuri P,DiRenzo J.MiR203 mediates subversion of stem cell properties during mammary epithelial differentiation via repression of ΔNP63α and promotes mesenchymal-to-epithelial transition..Cell Death Dis2013;4:e514 PMCID:PMC3734833

[218] Taube JH,Lu E.Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties..Sci Rep2013;3:2687 PMCID:PMC3776231

[219] Wellner U,Burk UC.The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs..Nat Cell Biol2009;11:1487-95

[220] Sempere LF,Silahtaroglu A.Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer..Cancer Res2007;67:11612-20

[221] Chao C-H,Wu M-J.MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis..J Clin Invest2014;124:3093-106 PMCID:PMC4071406

[222] Dong L,Xin C,Sun P.MicroRNA-139 Suppresses the Tumorigenicity of Triple Negative Breast Cancer Cells by Targeting SOX8..Cancer Manag Res2020;12:9417-28 PMCID:PMC7535124

[223] Chen H,Zhang L.MicroRNA-200c Inhibits the Metastasis of Triple-Negative Breast Cancer by Targeting ZEB2, an Epithelial-Mesenchymal Transition Regulator..Ann Clin Lab Sci2020;50:519-27

[224] Sulaiman A,Han X,Wang L.CSCs in Breast Cancer-One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs..Cancers2019;11:1128 PMCID:PMC6721464