The roles of ncRNAs and histone-modifiers in regulating breast cancer stem cells

Abstract

Cancer stem cells (CSCs), a subpopulation of cancer cells with ability of initiating tumorigenesis, exist in many kinds of tumors including breast cancer. Cancer stem cells contribute to treatment resistance and relapse. Conventional treatments only kill differentiated cancer cells, but spare CSCs. Combining conventional treatments with therapeutic drugs targeting to CSCs will eradicate cancer cells more efficiently. Studying the molecular mechanisms of CSCs regulation is essential for developing new therapeutic strategies. Growing evidences showed CSCs are regulated by non-coding RNA (ncRNA) including microRNAs and long non-coding RNAs (lncRNAs), and histone-modifiers, such as let-7, miR-93, miR-100, HOTAIR, Bmi-1 and EZH2. Herein we review the roles of microRNAs, lncRNAs and histonemodifiers especially Polycomb family proteins in regulating breast cancer stem cells (BCSCs).

Keywords

breast cancer stem cells / microRNA / lncRNA / histone-modifier / Polycomb group proteins

References

[1] Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

[2] Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400

[3] Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N(2013) A microRNA miR- 34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell 12:602–615

[4] Cai WY, Wei TZ, Luo QC, Wu QW, Liu QF, Yang M, Ye GD, Wu JF, Chen YY, Sun GB (2013) The Wnt-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion. J Cell Sci 126:2877–2889

[5] Cao R, Zhang Y (2004) SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EEDEZH2 complex. Mol Cell 15:57–67

[6] Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, Ping B, Otte AP, Hung MC (2005) Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310:306–310

[7] Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN, Hung MC (2011) EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell 19:86–100

[8] Cho JH, Dimri M, Dimri GP (2013) A positive feedback loop regulates the expression of polycomb group protein BMI1 via WNT signaling pathway. J Biol Chem 288:3406–3418

[9] Clement V, Sanchez P, de Tribolet N, Radovanovic I, i Altaba R (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17:165–172

[10] Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 109:2784–2789

[11] D’Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM, Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley SJ(2015). Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol Cancer Ther

[12] Deng L, Shang L, Bai S, Chen J, He X, Trevino RM, Chen S, Li X, Meng X, Yu B (2014) microRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development. Cancer Res 74:6648–6660

[13] Dong CF, Wu YD, Yao J, Wang YF, Yu YH, Rychahou PG, Evers BM, Zhou BP (2012) G9a interacts with Snail and is critical for snail-mediated E-cadherin repression in human breast cancer. J Clin Investig 122:1469–1486

[14] Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270

[15] Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S (2007) shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1:13

[16] Finlay-Schultz J, Cittelly DM, Hendricks P, Patel P, Kabos P, Jacobsen BM, Richer JK, Sartorius CA (2014) Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a. Oncogene 0

[17] Ginestier C, Wicha MS (2007) Mammary stem cell number as a determinate of breast cancer risk. Breast Cancer Res 9:109

[18] Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu SL (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567

[19] Guil S, Soler M, Portela A, Carrere J, Fonalleras E, Gomez A, Villanueva A, Esteller M (2012) Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol 19:664–670

[20] Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464:1071–1076

[21] Gwak JM, Kim HJ, Kim EJ, Chung YR, Yun S, Seo AN, Lee HJ, Park SY (2014) MicroRNA-9 is associated with epithelial-mesenchymal transition, breast cancer stem cell phenotype, and tumor progression in breast cancer. Breast Cancer Res Treat 147:39–49

[22] Han M, Liu M, Wang Y, Mo Z, Bi X, Liu Z, Fan Y, Chen X, Wu C (2012a) Re-expression of miR-21 contributes to migration and invasion by inducing epithelial-mesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells. Mol Cell Biochem 363:427–436

[23] Han M, Wang Y, Liu M, Bi X, Bao J, Zeng N, Zhu Z, Mo Z, Wu C, Chen X(2012b) MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia-inducible factor-1alpha expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci 103:1058–1064

[24] Han ML, Liu MR, Wang YM, Chen X, Xu JL, Sun Y, Zhao LY, Qu HB, Fan YM, Wu CY (2012c) Antagonism of miR-21 reverses epithelial-mesenchymal transition and cancer stem cell phenotype through AKT/ERK1/2 inactivation by targeting PTEN. PLoS ONE 7:e39520

[25] Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, Kalemkerian GP, Wicha MS (2013) Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin Cancer Res 19:1972–1980

[26] He J, Shen L, Wan M, Taranova O, Wu H, Zhang Y (2013) Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol 15:373–384

[27] Heo I, Joo C, Cho J, Ha M, Han J, Kim VN (2008) Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 32:276–284

[28] Hou Y, Song L, Zhu P, Zhang B, Tao Y, Xu X, Li F, Wu K, Liang J, Shao D et al (2012) Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell 148:873–885

[29] Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, Zhao L, Zhang Y, Huang B, Lu J (2014) LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis 5:e1287

[30] Hwang-Verslues WW, Chang PH, Wei PC, Yang CY,Huang CK , Kuo WH, Shew JY,Chang KJ , Lee EYHP, Lee WH (2011) miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1. Oncogene 30:2463–2474

[31] Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN (2009) MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2:r62

[32] Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K (2010) Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 39:761–772

[33] Isobe T, Hisamori S, Hogan DJ, Zabala M, Hendrickson DG, Dalerba P, Cai S, Scheeren F, Kuo AH, Sikandar SS(2014) miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife 3:e01977

[34] Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H(2004) Enhanced selfrenewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21:843–851

[35] Jung HY, Jun S, Lee M, Kim HC, Wang X, Ji H, McCrea PD, Park JI (2013) PAF and EZH2 induce Wnt/beta-catenin signaling hyperactivation. Mol Cell 52:193–205

[36] Ke J, Zhao Z, Hong SH, Bai S, He Z, Malik F, Xu J, Zhou L, Chen W, Martin-Trevino R (2015) Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells. Oncotarget 6:3709

[37] Kerppola TK (2009) Polycomb group complexes–many combinations, many functions. Trends Cell Biol 19:692–704

[38] Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH (2010) Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 176:2911–2920

[39] Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139

[40] Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, Oh YT, Kim H, Rheey J, Nakano I (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23:839–852

[41] Kim SK, Lee H, Han K, Kim SC, Choi Y, Park SW, Bak G, Lee Y, Choi JK, Kim TK (2014) SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs. Cell Stem Cell 15:735–749

[42] Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100:11606–11611

[43] Kottakis F, Polytarchou C, Foltopoulou P, Sanidas I, Kampranis SC, Tsichlis PN (2011) FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell 43:285–298

[44] Kottakis F, Foltopoulou P, Sanidas I, Keller P, Wronski A, Dake BT, Ezell SA, Shen Z, Naber SP, Hinds PW (2014) NDY1/ KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells. Cancer Res 74:3935–3946

[45] Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T,Cao LX ,Baiazitov R, Du W, Sydorenko N (2014) Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 20:29–36

[46] Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Cacerescortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid-leukemia after transplantation into Scid mice. Nature 367:645–648

[47] Lara-Astiaso D, Weiner A, Lorenzo-Vivas E, Zaretsky I, Jaitin DA, David E, Keren-Shaul H, Mildner A, Winter D, Jung S (2014) Immunogenetics. Chromatin state dynamics during blood formation. Science 345:943–949

[48] Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–260

[49] Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15:501–513

[50] Li Q, Eades G, Yao Y, Zhang Y, Zhou Q (2014) Characterization of a stem-like subpopulation in basal-like ductal carcinoma in situ (DCIS) lesions. J Biol Chem 289:1303–1312

[51] Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS (2006) Hedgehog signaling and Bmi-1 regulate selfrenewal of normal and malignant human mammary stem cells. Cancer Res 66:6063–6071

[52] Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C,Honorio S (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215

[53] Liu S, Patel SH, Ginestier C, Ibarra I, Martin-Trevino R, Bai S, McDermott SP, Shang L, Ke J, Ou SJ (2012) MicroRNA93 regulates proliferation and differentiation of normal and malignant breast stem cells. PLoS Genet 8:e1002751

[54] Liu SL, Cong Y, Wang D, Sun Y, Deng L, Liu YJ, Martin-Trevino R, Shang L, McDermott SP, Landis MD (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2:78–91

[55] Lukacs RU, Memarzadeh S, Wu H, Witte ON (2010) Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 7:682–693

[56] Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–2556

[57] Ma L, Teruya-Feldstein J, Weinberg RA (2008) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer (vol 449, p. 682, 2007). Nature 455:256

[58] Michalak EM, Nacerddine K, Pietersen A, Beuger V, Pawlitzky I, Cornelissen-Steijger P, Wientjens E, Tanger E, Seibler J, van Lohuizen M et al (2013) Polycomb group gene Ezh2 regulates mammary gland morphogenesis and maintains the luminal progenitor pool. Stem Cells 31:1910–1920

[59] Monteiro J, Gaspar C, Richer W, Franken PF, Sacchetti A, Joosten R, Idali A, Brandao J, Decraene C, Fodde R (2014) Cancer stemness in Wnt-driven mammary tumorigenesis. Carcinogenesis 35:2–13

[60] Neven E, De Schutter TM, Dams G, Gundlach K, Steppan S, Buechel J, Passlick-Deetjen J, D’Haese PC, Behets GJ (2014) A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats. PLoS ONE 9:e107067

[61] Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA (2009) MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer 9:293–302

[62] Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA, Ma J, Minden MD, Downing JR, Dick JE (2011) Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469:362–367

[63] Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, Mo YY, Iiizumi-Gairani M, Hirota S, Liu Y(2013) miR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res 73:1434–1444

[64] Padua Alves C, Fonseca AS, Muys BR, de Barros ELBR, Burger MC, de Souza JE, Valente V, Zago MA, Silva WA Jr (2013) Brief report: the lincRNA Hotair is required for epithelial-to-mesenchymal transition and stemness maintenance of cancer cell lines. Stem Cells 31:2827–2832

[65] Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, Miele L (2010) Targeting Notch to target cancer stem cells. Clin Cancer Res 16:3141–3152

[66] Park EY, Chang E, Lee EJ, Lee HW, Kang HG, Chun KH, Woo YM, Kong HK, Ko JY, Suzuki H(2014) Targeting of miR34a- NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res 74:7573–7582

[67] Pasini D, Bracken AP, Jensen MR, Denchi EL, Helin K (2004) Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061–4071

[68] Patani N, Jiang WG, Newbold RF, Mokbel K (2011) Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer. Anticancer Res 31:4115–4125

[69] Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/ progenitor cell properties. Cancer Res 65:5506–5511

[70] Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

[71] Schade B, Lesurf R, Sanguin-Gendreau V, Bui T, Deblois G, O’Toole SA, Millar EKA, Zardawi SJ, Lopez-Knowles E, Sutherland RL (2013) beta-Catenin signaling is a critical event in ErbB2- mediated mammary tumor progression. Cancer Res 73:4474–4487

[72] Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349

[73] Schwartz YB, Pirrotta V (2013) A new world of polycombs: unexpected partnerships and emerging functions. Nat Rev Genet 14:853–864

[74] Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592–603

[75] Simon JA, Kingston RE (2009) Mechanisms of Polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 10:697–708

[76] Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

[77] Song SJ, Poliseno L, Song MS, Ala U, Webster K, Ng C, Beringer G, Brikbak NJ, Yuan X, Cantley LC(2013) MicroRNAantagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154:311–324

[78] Stegle O, Teichmann SA, Marioni JC (2015) Computational and analytical challenges in single-cell transcriptomics. Nat Rev Genet 16:133–145

[79] Takahashi RU, Miyazaki H, Takeshita F, Yamamoto Y, Minoura K, Ono M, Kodaira M, Tamura K, Mori M, Ochiya T (2015) Loss of microRNA-27b contributes to breast cancer stem cell generation by activating ENPP1. Nat Commun 6:7318

[80] Tang W, Yu F, Yao H, Cui X, Jiao Y, Lin L, Chen J, Yin D, Song E, Liu Q (2014) miR-27a regulates endothelial differentiation of breast cancer stem like cells. Oncogene 33:2629–2638

[81] Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H (2012) RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3 (vol 148, p. 664, 2012). Cell 149:1647–1648

[82] Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY (2010) Long noncoding RNA as modular scaffold of histone modification complexes. Science 329:689–693

[83] Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, Jin W, Zhang Y (2013) MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res 73:6046–6055

[84] Tzatsos A, Paskaleva P, Lymperi S, Contino G, Stoykova S, Chen Z, Wong KK, Bardeesy N (2011) Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells. J Biol Chem 286:33061–33069

[85] Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

[86] Wang L, Zhao Z, Meyer MB, Saha S, Yu M, Guo A, Wisinski KB, Huang W, Cai W, Pike JW (2014) CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25:21–36

[87] Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, Yan X, Ye B, Li C, Xia P (2015) The long noncoding RNA lncTCF7 promotes selfrenewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 16:413–425

[88] Wright MH, Robles AI, Herschkowitz JI, Hollingshead MG, Anver MR, Perou CM, Varticovski L (2008) Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1. Mol Cancer 7:29

[89] Xing Z, Lin A, Li C, Liang K, Wang S, Liu Y, Park PK, Qin L, Wei Y, Hawke DH (2014) lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell 159:1110–1125

[90] Xiong YJ, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51:836–845

[91] Yamamoto S, Wu ZH, Russnes HG, Takagi S, Peluffo G, Vaske C, Zhao X, Vollan HKM, Maruyama R, Ekram MB (2014) JARID1B Is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762–777

[92] Yan KS, Chia LA, Li XN, Ootani A, Su J, Lee JY, Su N, Luo YL, Heilshorn SC, Amieva MR (2012) The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 109:466–471

[93] Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT, Fan ST (2008) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13:153–166

[94] Yeung TM, Gandhi SC, Bodmer WF (2011) Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci USA 108:4382–4387

[95] Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J(2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123

[96] Yu F, Deng H, Yao H, Liu Q, Su F, Song E (2010) Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumorinitiating cells. Oncogene 29:4194–4204

[97] Yu FY, Jiao Y, Zhu YH, Wang Y, Zhu JD, Cui XY, Liu YJ, He YH, Park EY, Zhang HY (2012) MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells. J Biol Chem 287:465–473

[98] Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC (2014) A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25:666–681

[99] Zhang Y, Eades G, Yao Y, Li Q, Zhou Q (2012) Estrogen receptor alpha signaling regulates breast tumor-initiating cells by downregulating miR-140 which targets the transcription factor SOX2. J Biol Chem 287:41514–41522

[100] Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, Jiang L, Zhang Y, Dou J (2014a) MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells 32:2858–2868

[101] Zhang JS, Zhang PJ, Wang L, Piao HL, Ma L (2014b) Long noncoding RNA HOTAIR in carcinogenesis and metastasis. Acta Biochim Biophys Sin 46:1–5

[102] Zhang M, Wang Y, Jones S, Sausen M, McMahon K, Sharma R, Wang Q, Belzberg AJ, Chaichana K, Gallia GL (2014c) Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet 46:1170–1172

[103] Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D (2009) Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458:776–779

[104] Zhao D, Mo Y, Li MT, Zou SW, Cheng ZL, Sun YP, Xiong Y, Guan KL, Lei QY (2014) NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J Clin Investig 124:5453–5465

[105] Zhu Y, Yu F, Jiao Y, Feng J, Tang W, Yao H, Gong C, Chen J, Su F, Zhang Y (2011) Reduced miR-128 in breast tumor-initiating cells induces chemotherapeutic resistance via Bmi-1 and ABCC5. Clin Cancer Res 17:7105–7115

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