SpringerLink
Log in

Breast Cancer Stem Cells

  • Chapter
  • First Online:
Molecular Pathology of Breast Cancer

  • 1399 Accesses

Abstract

Cancer stem cells (CSCs) represent a heterogeneous subpopulation of cancer cells within tumors. CSCs divide asymmetrically to generate daughter cells that either have CSC characteristics including self-renewal, or differentiation potential to form neoplastic cells which constitute most of the tumor. These characteristics suggest that the cells may play an important role in tumor initiation, and development of chemo-resistance. These characteristics are evident in the ability of CSCs to seed new tumors upon transplantation in experimental animal models. In this chapter, we describe the evidence around the role of CSCs in breast cancer. A brief overview of the methods and markers used to identify these cells is also provided. More importantly, we present the data regarding the signaling pathways that are implicated in the aggressiveness associated with CSCs. Lastly, we discuss the strategies that can be used for targeting these pathways for therapeutic purposes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Abdullah LN, Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2(1):3. doi:10.1186/2001-1326-2-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Abiola M, Favier M, Christodoulou-Vafeiadou E, Pichard AL, Martelly I, Guillet-Deniau I (2009) Activation of Wnt/beta-catenin signaling increases insulin sensitivity through a reciprocal regulation of Wnt10b and SREBP-1c in skeletal muscle cells. PLoS ONE 4(12):e8509. doi:10.1371/journal.pone.0008509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Abubaker K, Luwor RB, Zhu H, McNally O, Quinn MA, Burns CJ, Thompson EW, Findlay JK, Ahmed N (2014) Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden. BMC Cancer 14:317. doi:10.1186/1471-2407-14-317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, Vielh P, Larsen AK, Thiery JP, Sabbah M, Chouaib S (2015) Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene 34(17):2261–2271. doi:10.1038/onc.2014.151

    Article  CAS  PubMed  Google Scholar 

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988. doi:10.1073/pnas.0530291100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alderton GK (2012) Metastasis: STAT3 promotes premetastatic niche formation. Nat Rev Cancer 12(7):453. doi:10.1038/nrc3313

    Google Scholar 

  • Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB (2007) Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Investig 117(2):326–336. doi:10.1172/JCI28833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ambs S, Merriam WG, Bennett WP, Felley-Bosco E, Ogunfusika MO, Oser SM, Klein S, Shields PG, Billiar TR, Harris CC (1998) Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res 58(2):334–341

    CAS  PubMed  Google Scholar 

  • Amoyel M, Anderson AM, Bach EA (2014) JAK/STAT pathway dysregulation in tumors: a Drosophila perspective. Semin Cell Dev Biol 28:96–103. doi:10.1016/j.semcdb.2014.03.023

    Article  CAS  PubMed  Google Scholar 

  • Angeloni V, Tiberio P, Appierto V, Daidone MG (2015) Implications of stemness-related signaling pathways in breast cancer response to therapy. Semin Cancer Biol 31:43–51. doi:10.1016/j.semcancer.2014.08.004

    Article  CAS  PubMed  Google Scholar 

  • Anglani F, Mezzabotta F, Ceol M, Cristofaro R, Del Prete D, D’Angelo A (2010) The regenerative potential of the kidney: what can we learn from developmental biology? Stem Cell Rev 6(4):650–657. doi:10.1007/s12015-010-9186-6

    Article  PubMed  Google Scholar 

  • Anjomshoaa A, Nasri S, Humar B, McCall JL, Chatterjee A, Yoon HS, Mcnoe L, Black MA, Reeve AE (2009) Slow proliferation as a biological feature of colorectal cancer metastasis. Br J Cancer 101(5):822–828. doi:10.1038/sj.bjc.6605229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker M (2012) Cancer stem cells tracked. Nature 488(7409):13–14. doi:10.1038/488013a

    Article  CAS  PubMed  Google Scholar 

  • Behari J (2010) The Wnt/beta-catenin signaling pathway in liver biology and disease. Expert Rev Gastroenterol Hepatol 4(6):745–756. doi:10.1586/egh.10.74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382(6592):638–642. doi:10.1038/382638a0

    Article  CAS  PubMed  Google Scholar 

  • Bergstein I, Schultz R, Osborne MP, Welcsh PL, Bowcock AM, Brown AM (1995) Investigation of the possible role of WNT genes in human breast cancer. Ann N Y Acad Sci 768:257

    Article  CAS  PubMed  Google Scholar 

  • Bertrand G, Maalouf M, Boivin A, Battiston-Montagne P, Beuve M, Levy A, Jalade P, Fournier C, Ardail D, Magne N, Alphonse G, Rodriguez-Lafrasse C (2014) Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev 10(1):114–126. doi:10.1007/s12015-013-9467-y

    Article  CAS  PubMed  Google Scholar 

  • Bilir B, Kucuk O, Moreno CS (2013) Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells. J Trans Med 11:280. doi:10.1186/1479-5876-11-280

    Article  CAS  Google Scholar 

  • Blau HM, Brazelton TR, Weimann JM (2001) The evolving concept of a stem cell: entity or function? Cell 105(7):829–841

    Article  CAS  PubMed  Google Scholar 

  • Brabletz T (2012) To differentiate or not—routes towards metastasis. Nat Rev Cancer 12(6):425–436. doi:10.1038/nrc3265

    Article  CAS  PubMed  Google Scholar 

  • Bulut AS, Erden E, Sak SD, Doruk H, Kursun N, Dincol D (2005) Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of 151 cases. Virchows Archiv: Int J Pathol 447(1):24–30. doi:10.1007/s00428-005-1250-2

    Article  CAS  Google Scholar 

  • Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW, Huang EH (2009) Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 69(20):8208–8215. doi:10.1158/0008-5472.CAN-09-1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cavaleri F, Scholer HR (2003) Nanog: a new recruit to the embryonic stem cell orchestra. Cell 113(5):551–552

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Huang YH, Chen JL (2013) Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 34(6):732–740. doi:10.1038/aps.2013.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Q, Giedt M, Tang L, Harrison DA (2014) Tools and methods for studying the Drosophila JAK/STAT pathway. Methods 68(1):160–172. doi:10.1016/j.ymeth.2014.03.023

    Article  CAS  PubMed  Google Scholar 

  • Cheung AM, Wan TS, Leung JC, Chan LY, Huang H, Kwong YL, Liang R, Leung AY (2007) Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 21(7):1423–1430. doi:10.1038/sj.leu.2404721

    Article  CAS  PubMed  Google Scholar 

  • Cho RW, Wang X, Diehn M, Shedden K, Chen GY, Sherlock G, Gurney A, Lewicki J, Clarke MF (2008) Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26(2):364–371. doi:10.1634/stemcells.2007-0440

    Article  CAS  PubMed  Google Scholar 

  • Choi DS, Blanco E, Kim YS, Rodriguez AA, Zhao H, Huang TH, Chen CL, ** G, Landis MD, Burey LA, Qian W, Granados SM, Dave B, Wong HH, Ferrari M, Wong ST, Chang JC (2014) Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 32(9):2309–2323. doi:10.1002/stem.1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung SS, Vadgama JV (2015) Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down-regulation of STAT3-NFkappaB signaling. Anticancer Res 35(1):39–46

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cleary AS, Leonard TL, Gestl SA, Gunther EJ (2014) Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508(7494):113–117. doi:10.1038/nature13187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3):469–480. doi:10.1016/j.cell.2006.10.018

    Article  CAS  PubMed  Google Scholar 

  • Clevers H, Loh KM, Nusse R (2014) Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science 346(6205):1248012. doi:10.1126/science.1248012

    Google Scholar 

  • Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149(6):1192–1205. doi:10.1016/j.cell.2012.05.012

    Article  CAS  PubMed  Google Scholar 

  • Cojoc M, Mabert K, Muders MH, Dubrovska A (2015) A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms. Semin Cancer Biol 31:16–27. doi:10.1016/j.semcancer.2014.06.004

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A 109(8):2784–2789. doi:10.1073/pnas.1018866109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Constantinescu S (2003) Stemness, fusion and renewal of hematopoietic and embryonic stem cells. J Cell Mol Med 7(2):103–112

    Article  CAS  PubMed  Google Scholar 

  • Creighton CJ, Chang JC, Rosen JM (2010) Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mamm Gland Biol Neoplasia 15(2):253–260. doi:10.1007/s10911-010-9173-1

    Article  Google Scholar 

  • Creighton CJ, Li XX, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang XM, He XP, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 106(33):13820–13825. doi:10.1073/pnas.0905718106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Croker AK, Allan AL (2012) Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44(+) human breast cancer cells. Breast Cancer Res Treat 133(1):75–87. doi:10.1007/s10549-011-1692-y

    Article  CAS  PubMed  Google Scholar 

  • Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104. doi:10.1038/cr.2013.153

    Article  CAS  PubMed  Google Scholar 

  • Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Vellon L, Menendez JA (2011) Autophagy positively regulates the CD44(+) CD24(−/low) breast cancer stem-like phenotype. Cell Cycle 10(22):3871–3885. doi:10.4161/cc.10.22.17976

    Article  CAS  PubMed  Google Scholar 

  • Dave B, Granados-Principal S, Zhu R, Benz S, Rabizadeh S, Soon-Shiong P, Yu KD, Shao Z, Li X, Gilcrease M, Lai Z, Chen Y, Huang TH, Shen H, Liu X, Ferrari M, Zhan M, Wong ST, Kumaraswami M, Mittal V, Chen X, Gross SS, Chang JC (2014) Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci U S A 111(24):8838–8843. doi:10.1073/pnas.1320769111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dave B, Landis MD, Tweardy DJ, Chang JC, Dobrolecki LE, Wu MF, Zhang X, Westbrook TF, Hilsenbeck SG, Liu D, Lewis MT (2012) Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model. PLoS ONE 7(8):e30207. doi:10.1371/journal.pone.0030207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deshpande AJ, Cusan M, Rawat VPS, Reuter H, Krause A, Pott C, Quintanilla-Martinez L, Kakadia P, Kuchenbauer F, Ahmed F, Delabesse E, Hahn M, Lichter P, Kneba M, Hiddemann W, Macintyre E, Mecucci C, Ludwig WD, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C (2006) Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell 10(5):363–374. doi:10.1016/j.ccr.2006.08.023

    Article  CAS  PubMed  Google Scholar 

  • Eyler CE, Wu Q, Yan K, MacSwords JM, Chandler-Militello D, Misuraca KL, Lathia JD, Forrester MT, Lee J, Stamler JS, Goldman SA, Bredel M, McLendon RE, Sloan AE, Hjelmeland AB, Rich JN (2011) Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell 146(1):53–66. doi:10.1016/j.cell.2011.06.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, Andre S, Piccart M, Campone M, Brain E, Macgrogan G, Petit T, Jassem J, Bibeau F, Blot E, Bogaerts J, Aguet M, Bergh J, Iggo R, Delorenzi M (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. NatMed 15(1):68–74. doi:10.1038/nm.1908. (nm.1908 [pii])

    Google Scholar 

  • Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L (1999) A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94(4):1192–1200

    CAS  PubMed  Google Scholar 

  • Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D (1993) Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 82(11):3241–3249

    CAS  PubMed  Google Scholar 

  • Finbloom DS, Silver K, Newsome DA, Gunkel R (1985) Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity. J Rheumatol 12(4):692–694

    CAS  PubMed  Google Scholar 

  • Firat E, Weyerbrock A, Gaedicke S, Grosu AL, Niedermann G (2012) Chloroquine or chloroquine-PI3 K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem-like glioma cells. PLoS ONE 7(10):e47357. doi:10.1371/journal.pone.0047357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Formelli F, Cleris L (1993) Synthetic retinoid fenretinide is effective against a human ovarian-carcinoma xenograft and potentiates cisplatin activity. Cancer Res 53(22):5374–5376

    CAS  PubMed  Google Scholar 

  • Gil-Sanz C, Espinosa A, Fregoso SP, Bluske KK, Cunningham CL, Martinez-Garay I, Zeng H, Franco SJ, Muller U (2015) Lineage Tracing Using Cux2-Cre and Cux2-CreERT2 Mice. Neuron 86(4):1091–1099. doi:10.1016/j.neuron.2015.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu SL, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. doi:10.1016/j.stem.2007.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giuliano M, Schifp R, Osborne CK, Trivedi MV (2011) Biological mechanisms and clinical implications of endocrine resistance in breast cancer. Breast 20(Suppl 3):S42–49. doi:10.1016/S0960-9776(11)70293-4

    Article  PubMed  Google Scholar 

  • Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12. doi:10.1002/path.2697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glynn SA, Boersma BJ, Dorsey TH, Yi M, Yfantis HG, Ridnour LA, Martin DN, Switzer CH, Hudson RS, Wink DA, Lee DH, Stephens RM, Ambs S (2010) Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J Clin Investig 120(11):3843–3854. doi:10.1172/JCI42059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong C, Bauvy C, Tonelli G, Yue W, Delomenie C, Nicolas V, Zhu Y, Domergue V, Marin-Esteban V, Tharinger H, Delbos L, Gary-Gouy H, Morel AP, Ghavami S, Song E, Codogno P, Mehrpour M (2013) Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene 32(18):2261–2272, 2272e, 2261–2211. doi:10.1038/onc.2012.252

    Google Scholar 

  • Granados-Principal S, Liu Y, Guevara ML, Blanco E, Choi DS, Qian W, Patel T, Rodriguez AA, Cusimano J, Weiss HL, Zhao H, Landis MD, Dave B, Gross SS, Chang JC (2015) Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer. Breast Cancer Res 17:25. doi:10.1186/s13058-015-0527-x. ARTN 25

  • Grunt ThW, Dittrich E, Offterdinger M, Schneider SM, Dittrich C, Huber H (1998) Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells. Br J Cancer 78(1):79–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison DA (2012) The Jak/STAT pathway. Cold Spring Harb Perspect Biol 4(3). doi:10.1101/cshperspect.a011205

    Google Scholar 

  • Heppner GH (1984) Tumor heterogeneity. Cancer Res 44(6):2259–2265

    CAS  PubMed  Google Scholar 

  • Heppner GH, Chong YC, Fulton AM (1989) Host-mediated induction of tumor heterogeneity. Ann N Y Acad Sci 567:234–242

    Article  CAS  PubMed  Google Scholar 

  • Heppner GH, Miller BE (1989) Therapeutic implications of tumor heterogeneity. Semin Oncol 16(2):91–105

    CAS  PubMed  Google Scholar 

  • Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76. doi:10.1186/gb-2007-8-5-r76. (gb-2007-8-5-r76 [pii])

    Google Scholar 

  • Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Maelandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A (2014) Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discovery 4(9):998–1013. doi:10.1158/2159-8290.CD-14-0001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopper RA, Garthwaite J (2006) Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J Neurosci 26(45):11513–11521. doi:10.1523/JNEUROSCI.2259-06.2006

    Article  CAS  PubMed  Google Scholar 

  • Hsu HS, Lin JH, Hsu TW, Su K, Wang CW, Yang KY, Chiou SH, Hung SC (2012) Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer 75(2):167–177. doi:10.1016/j.lungcan.2011.07.001

    Article  PubMed  Google Scholar 

  • Hsu YC (2015) Theory and practice of lineage tracing. Stem Cells 33(11):3197–3204. doi:10.1002/stem.2123

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Smyth GK (2009) ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 347(1–2):70–78. doi:10.1016/j.jim.2009.06.008

    CAS  PubMed  Google Scholar 

  • Hughes K, Watson CJ (2012) The spectrum of STAT functions in mammary gland development. Jakstat 1(3):151–158. doi:10.4161/jkst.19691

    PubMed  PubMed Central  Google Scholar 

  • Ignarro LJ (1990) Nitric oxide. A novel signal transduction mechanism for transcellular communication. Hypertension 16(5):477–483

    Article  CAS  PubMed  Google Scholar 

  • Illa-Bochaca I, Fernandez-Gonzalez R, Shelton DN, Welm BE, Ortiz-de-Solorzano C, Barcellos-Hoff MH (2010) Limiting-dilution transplantation assays in mammary stem cell studies. Methods Mol Biol 621:29–47. doi:10.1007/978-1-60761-063-2_2

    Article  CAS  PubMed  Google Scholar 

  • Ivashkiv LB (2000) Jak-STAT signaling pathways in cells of the immune system. Rev Immunogenet 2(2):220–230

    CAS  PubMed  Google Scholar 

  • Ivashkiv LB, Hu X (2004) Signaling by STATs. Arthritis Res Ther 6(4):159–168. doi:10.1186/ar1197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jamal-Hanjani M, Quezada SA, Larkin J, Swanton C (2015) Translational implications of tumor heterogeneity. Clin Cancer Res 21(6):1258–1266. doi:10.1158/1078-0432.CCR-14-1429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janku F, McConkey DJ, Hong DS, Kurzrock R (2011) Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8(9):528–539. doi:10.1038/nrclinonc.2011.71

    Article  CAS  PubMed  Google Scholar 

  • Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, **ng LX, Wang HJ, Liu ZQ, Su Y, Stass SA, Katz RL (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7(3):330–338. doi:10.1158/1541-7786.Mcr-08-0393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kahn M (2014) Can we safely target the WNT pathway? Nat Rev Drug Discov 13(7):513–532. doi:10.1038/nrd4233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalemkerian GP, Ou X (1999) Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines. Cancer Chemother Pharmacol 43(2):145–150. doi:10.1007/s002800050875

    Article  CAS  PubMed  Google Scholar 

  • Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y (2004) Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 6(6):547–554. doi:10.1038/ncb1138

    Article  CAS  PubMed  Google Scholar 

  • Kazi AA, Gilani RA, Schech AJ, Chumsri S, Sabnis G, Shah P, Goloubeva O, Kronsberg S, Brodie AH (2014) Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer. Breast Cancer Res 16(1):R15. doi:10.1186/bcr3609

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Keitel U, Scheel A, Thomale J, Halpape R, Kaulfuss S, Scheel C, Dobbelstein M (2014) Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation. Oncotarget 5(23):11778–11791. doi:10.18632/oncotarget.2634

    Article  PubMed  PubMed Central  Google Scholar 

  • Kenific CM, Thorburn A, Debnath J (2010) Autophagy and metastasis: another double-edged sword. Curr Opin Cell Biol 22(2):241–245. doi:10.1016/j.ceb.2009.10.008

    Article  CAS  PubMed  Google Scholar 

  • Kim MS, Lee WS, Jeong J, Kim SJ, ** W (2015) Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3 K/AKT signaling in breast cancer. Oncotarget 6(37):40158–40171. doi:10.18632/oncotarget.5522

    PubMed  PubMed Central  Google Scholar 

  • Kimura-Yoshida C, Nakano H, Okamura D, Nakao K, Yonemura S, Belo JA, Aizawa S, Matsui Y, Matsuo I (2005) Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm. Dev Cell 9(5):639–650. doi:10.1016/j.devcel.2005.09.011

    Article  CAS  PubMed  Google Scholar 

  • Kolosenko I, Grander D, Tamm KP (2014) IL-6 activated JAK/STAT3 pathway and sensitivity to Hsp90 inhibitors in multiple myeloma. Curr Med Chem 21(26):3042–3047

    Article  CAS  PubMed  Google Scholar 

  • Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75

    PubMed  Google Scholar 

  • Kretzschmar K, Watt FM (2012) Lineage tracing. Cell 148(1–2):33–45. doi:10.1016/j.cell.2012.01.002

    Article  CAS  PubMed  Google Scholar 

  • Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442(7104):818–822. doi:10.1038/nature04980

    Article  CAS  PubMed  Google Scholar 

  • Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27(9):2059–2068. doi:10.1002/stem.154

    Article  CAS  PubMed  Google Scholar 

  • 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(6464):645–648. doi:10.1038/367645a0

    Article  CAS  PubMed  Google Scholar 

  • Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E, Chung IY, Kim IA, Kim EJ, Choi Y, Ryu HS, Park SY (2011) An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 104(11):1730–1738. doi:10.1038/bjc.2011.159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679. doi:10.1093/jnci/djn123

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE (2003) Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 100(26):15853–15858. doi:10.1073/pnas.2136825100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li YJ, Cui W, Tian ZJ, Hao YM, Du J, Liu F, Zhang H, Zu XG, Liu SY, **e RQ, Yang XH, Wu YZ, Chen L, An W (2004) Crosstalk between ERK1/2 and STAT3 in the modulation of cardiomyocyte hypertrophy induced by cardiotrophin-1. Chin Med J (Engl) 117(8):1135–1142

    CAS  Google Scholar 

  • Lin H, Lei J, Wininger D, Nguyen MT, Khanna R, Hartmann C, Yan WL, Huang SC (2003) Multilineage potential of homozygous stem cells derived from metaphase II oocytes. Stem Cells 21(2):152–161. doi:10.1634/stemcells.21-2-152

    Article  PubMed  Google Scholar 

  • Liu F, Shang Y, Chen SZ (2014a) Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells in vitro. Acta Pharmacol Sin 35(5):645–652. doi:10.1038/aps.2014.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, Martin-Trevino R, Shang L, McDermott SP, Landis MD, Hong S, Adams A, D’Angelo R, Ginestier C, Charafe-Jauffret E, Clouthier SG, Birnbaum D, Wong ST, Zhan M, Chang JC, Wicha MS (2014b) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2(1):78–91. doi:10.1016/j.stemcr.2013.11.009

    Article  CAS  PubMed  Google Scholar 

  • Livesey KM, Tang D, Zeh HJ, Lotze MT (2009) Autophagy inhibition in combination cancer treatment. Curr Opin Investig Drugs 10(12):1269–1279

    CAS  PubMed  Google Scholar 

  • Loibl S, Buck A, Strank C, von Minckwitz G, Roller M, Sinn HP, Schini-Kerth V, Solbach C, Strebhardt K, Kaufmann M (2005) The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur J Cancer 41(2):265–271. doi:10.1016/j.ejca.2004.07.010

    Article  CAS  PubMed  Google Scholar 

  • Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY (2008) Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6(7):1146–1153. doi:10.1158/1541-7786.MCR-08-0035

    Article  CAS  PubMed  Google Scholar 

  • Madjd Z, Mehrjerdi AZ, Sharifi AM, Molanaei S, Shahzadi SZ, Asadi-Lari M (2009) CD44+ cancer cells express higher levels of the anti-apoptotic protein Bcl-2 in breast tumours. Cancer Immun 9:4. (doi:090304 [pii])

    Google Scholar 

  • Maes H, Kuchnio A, Peric A, Moens S, Nys K, De Bock K, Quaegebeur A, Schoors S, Georgiadou M, Wouters J, Vinckier S, Vankelecom H, Garmyn M, Vion AC, Radtke F, Boulanger C, Gerhardt H, Dejana E, Dewerchin M, Ghesquiere B, Annaert W, Agostinis P, Carmeliet P (2014) Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26(2):190–206. doi:10.1016/j.ccr.2014.06.025

    Article  CAS  PubMed  Google Scholar 

  • Magni M, Shammah S, Schiro R, Mellado W, Dalla-Favera R, Gianni AM (1996) Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 87(3):1097–1103

    CAS  PubMed  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi:10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, Bloushtain-Qimron N, Kim JJ, Choudhury SA, Maruyama R, Wu Z, Gonen M, Mulvey LA, Bessarabova MO, Huh SJ, Silver SJ, Kim SY, Park SY, Lee HE, Anderson KS, Richardson AL, Nikolskaya T, Nikolsky Y, Liu XS, Root DE, Hahn WC, Frank DA, Polyak K (2011) The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors. J Clin Investig 121(7):2723–2735. doi:10.1172/JCI44745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Outschoorn UE, Lin Z, Ko YH, Goldberg AF, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F, Lisanti MP (2011) Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 10(15):2521–2528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Revollar G, Garay E, Martin-Tapia D, Nava P, Huerta M, Lopez-Bayghen E, Meraz-Cruz N, Segovia J, Gonzalez-Mariscal L (2015) Heterogeneity between triple negative breast cancer cells due to differential activation of Wnt and PI3 K/AKT pathways. Exp Cell Res 339(1):67–80. doi:10.1016/j.yexcr.2015.10.006

    Article  CAS  PubMed  Google Scholar 

  • Massi D, Franchi A, Sardi I, Magnelli L, Paglierani M, Borgognoni L, Maria Reali U, Santucci M (2001) Inducible nitric oxide synthase expression in benign and malignant cutaneous melanocytic lesions. J Pathol 194(2):194–200. doi:10.1002/1096-9896(200106)194:2<194:AID-PATH851>3.0.CO;2-S

    Article  CAS  PubMed  Google Scholar 

  • Mentink RA, Middelkoop TC, Rella L, Ji N, Tang CY, Betist MC, van Oudenaarden A, Korswagen HC (2014) Cell intrinsic modulation of Wnt signaling controls neuroblast migration in C. elegans. Dev Cell 31(2):188–201. doi:10.1016/j.devcel.2014.08.008

    Google Scholar 

  • Mitra A, Mishra L, Li S (2015) EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 6(13):10697–10711. doi:10.18632/oncotarget.4037

    Article  PubMed  PubMed Central  Google Scholar 

  • Mizushima N (2007) Autophagy: process and function. Genes Dev 21(22):2861–2873. doi:10.1101/gad.1599207

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. doi:10.1016/j.cell.2011.10.026

    Article  CAS  PubMed  Google Scholar 

  • Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86(3):391–399

    Article  CAS  PubMed  Google Scholar 

  • Moore MA, Shieh JH, Lee G (2006) Hematopoietic cells. Methods Enzymol 418:208–242. doi:10.1016/S0076-6879(06)18013-1

    Article  CAS  PubMed  Google Scholar 

  • Moore N, Lyle S (2011) Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance. J Oncol 2011. doi:10.1155/2011/396076

    Google Scholar 

  • Natarajan TG, Ganesan N, Fitzgerald KT (2010) Cancer stem cells and markers: new model of tumorigenesis with therapeutic implications. Cancer Biomark 9(1–6):65–99. doi:10.3233/CBM-2011-0173

    PubMed  Google Scholar 

  • Nathan C, **e QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78(6):915–918. doi:10.1016/0092-8674(94)90266-6. [pii]

    Google Scholar 

  • Nieto MA (2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376. doi:10.1146/annurev-cellbio-092910-154036

    Article  CAS  PubMed  Google Scholar 

  • Niwa H, Burdon T, Chambers I, Smith A (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12(13):2048–2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nusse R (2008) Wnt signaling and stem cell control. Cell Res 18(5):523–527. doi:10.1038/cr.2008.47

    Article  CAS  PubMed  Google Scholar 

  • Nusse R, Varmus HE (1982) Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31(1):99–109

    Article  CAS  PubMed  Google Scholar 

  • Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287(5785):795–801

    Article  CAS  PubMed  Google Scholar 

  • O’Brien CA, Kreso A, Jamieson CH (2010) Cancer stem cells and self-renewal. Clin Cancer Res 16(12):3113–3120. doi:10.1158/1078-0432.CCR-09-2824

    Article  PubMed  Google Scholar 

  • Odorico JS, Kaufman DS, Thomson JA (2001) Multilineage differentiation from human embryonic stem cell lines. Stem Cells 19(3):193–204. doi:10.1634/stemcells.19-3-193

    Article  CAS  PubMed  Google Scholar 

  • Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E (1996) TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 10(19):2462–2477

    Article  CAS  PubMed  Google Scholar 

  • Okayama H, Saito M, Oue N, Weiss JM, Stauffer J, Takenoshita S, Wiltrout RH, Hussain SP, Harris CC (2013) NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression. Int J Cancer J Int du Cancer 132(1):9–18. doi:10.1002/ijc.27644

    Article  CAS  Google Scholar 

  • Parajuli B, Fishel ML, Hurley TD (2014) Selective ALDH3A1 inhibition by benzimidazole analogues increase mafosfamide sensitivity in cancer cells. J Med Chem 57(2):449–461. doi:10.1021/jm401508p

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8(5):486–498. doi:10.1016/j.stem.2011.04.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells—what challenges do they pose? Nat Rev Drug Discov 13(7):497–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pettersson F, Colston KW, Dalgleish AG (2001) Retinoic acid enhances the cytotoxic effects of gemcitabine and cisplatin in pancreatic adenocarcinoma cells. Pancreas 23(3):273–279

    Article  CAS  PubMed  Google Scholar 

  • Pinto CA, Widodo E, Waltham M, Thompson EW (2013) Breast cancer stem cells and epithelial mesenchymal plasticity—Implications for chemoresistance. Cancer Lett 341(1):56–62. doi:10.1016/j.canlet.2013.06.003

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273. doi:10.1038/nrc2620

    Article  CAS  PubMed  Google Scholar 

  • Porrata LF, Litzow MR, Markovic SN (2001) Immune reconstitution after autologous hematopoietic stem cell transplantation. Mayo Clin Proc 76(4):407–412. doi:10.4065/76.4.407

    Article  CAS  PubMed  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598. doi:10.1038/nature07567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rangwala R, Leone R, Chang YC, Fecher LA, Schuchter LM, Kramer A, Tan KS, Heitjan DF, Rodgers G, Gallagher M, Piao S, Troxel AB, Evans TL, DeMichele AM, Nathanson KL, O’Dwyer PJ, Kaiser J, Pontiggia L, Davis LE, Amaravadi RK (2014) Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10(8):1369–1379. doi:10.4161/auto.29118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, Hong SM, Koorstra JB, Rajeshkumar NV, He X, Goggins M, Iacobuzio-Donahue C, Berman DM, Laheru D, Jimeno A, Hidalgo M, Maitra A, Matsui W (2010) Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 102(5):340–351. doi:10.1093/jnci/djp535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117(Pt 8):1281–1283. doi:10.1242/jcs.00963

    Article  CAS  PubMed  Google Scholar 

  • Reinert RB, Kantz J, Misfeldt AA, Poffenberger G, Gannon M, Brissova M, Powers AC (2012) Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice. PLoS ONE 7(3):e33529. doi:10.1371/journal.pone.0033529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R (1987) The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 50(4):649–657

    Article  CAS  PubMed  Google Scholar 

  • Rosen JM, Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324(5935):1670–1673. doi:10.1126/science.1171837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosfjord E, Lucas J, Li G, Gerber HP (2014) Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem Pharmacol 91(2):135–143. doi:10.1016/j.bcp.2014.06.008

    Article  CAS  PubMed  Google Scholar 

  • Rosselli M, Keller PJ, Dubey RK (1998) Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update 4(1):3–24

    Article  CAS  PubMed  Google Scholar 

  • Sanchez CG, Penfornis P, Oskowitz AZ, Boon**dasup AG, Cai DZ, Dhule SS, Rowan BG, Kelekar A, Krause DS, Pochampally RR (2011) Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis 32(7):964–972. doi:10.1093/carcin/bgr029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sauer B (1998) Inducible gene targeting in mice using the Cre/lox system. Methods 14(4):381–392. doi:10.1006/meth.1998.0593

    Article  CAS  PubMed  Google Scholar 

  • Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, Clevers H (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095):730–735. doi:10.1126/science.1224676

    Article  CAS  PubMed  Google Scholar 

  • Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing RC, Seagroves TN (2012) Hypoxia-inducible factor 1alpha promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res 14(1):R6. doi:10.1186/bcr3087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V (2013) Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 56:89–101. doi:10.1016/j.freeradbiomed.2012.11.010

    Article  CAS  PubMed  Google Scholar 

  • Siolas D, Hannon GJ (2013) Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res 73(17):5315–5319. doi:10.1158/0008-5472.Can-13-1069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skibinski A, Kuperwasser C (2015) The origin of breast tumor heterogeneity. Oncogene 34(42):5309–5316. doi:10.1038/onc.2014.475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith AG (2001) Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol 17:435–462. doi:10.1146/annurev.cellbio.17.1.435

    Article  CAS  PubMed  Google Scholar 

  • Sotelo J, Briceno E, Lopez-Gonzalez MA (2006) Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144(5):337–343

    Article  CAS  PubMed  Google Scholar 

  • Stechishin OD, Luchman HA, Ruan Y, Blough MD, Nguyen SA, Kelly JJ, Cairncross JG, Weiss S (2013) On-target JAK2/STAT3 inhibition slows disease progression in orthotopic xenografts of human glioblastoma brain tumor stem cells. Neuro Oncol 15(2):198–207. doi:10.1093/neuonc/nos302

    Article  CAS  PubMed  Google Scholar 

  • Switzer CH, Cheng RY, Ridnour LA, Glynn SA, Ambs S, Wink DA (2012) Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast Cancer Res 14(5):R125. doi:10.1186/bcr3319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH (1997) All-trans-retinoic acid in acute promyelocytic leukemia. New Engl J Med 337(15):1021–1028. doi:10.1056/NEJM199710093371501

    Article  CAS  PubMed  Google Scholar 

  • Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27(1):25–61

    Article  CAS  PubMed  Google Scholar 

  • Tefferi A, Gilliland DG (2005) The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc 80(7):947–958. doi:10.4065/80.7.947

    Article  CAS  PubMed  Google Scholar 

  • Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, Arcaroli JJ, Messersmith WA, Eckhardt SG (2012) Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 9(6):338–350. doi:10.1038/nrclinonc.2012.61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP (2015) Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep 5:10194. doi:10.1038/srep10194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. doi:10.1038/nrc822. (nrc822 [pii])

    Google Scholar 

  • Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S (1995) Nitric oxide synthase activity in human breast cancer. Br J Cancer 72(1):41–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiwari N, Gheldof A, Tatari M, Christofori G (2012) EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 22(3):194–207. doi:10.1016/j.semcancer.2012.02.013. (S1044-579X(12)00049-1 [pii])

    Google Scholar 

  • Tsuji T, Ibaragi S, Shima K, Hu MG, Katsurano M, Sasaki A, Hu GF (2008) Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res 68(24):10377–10386. doi:10.1158/0008-5472.CAN-08-1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vadakkan TJ, Landua JD, Bu W, Wei W, Li F, Wong ST, Dickinson ME, Rosen JM, Lewis MT, Zhang M (2014) Wnt-responsive cancer stem cells are located close to distorted blood vessels and not in hypoxic regions in a p53-null mouse model of human breast cancer. Stem Cells Transl Med 3(7):857–866. doi:10.5966/sctm.2013-0088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vainchenker W, Constantinescu SN (2013) JAK/STAT signaling in hematological malignancies. Oncogene 32(21):2601–2613. doi:10.1038/onc.2012.347

    Article  CAS  PubMed  Google Scholar 

  • van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136(19):3205–3214. doi:10.1242/dev.033910

    Article  PubMed  CAS  Google Scholar 

  • Van Camp JK, Beckers S, Zegers D, Van Hul W (2014) Wnt signaling and the control of human stem cell fate. Stem Cell Rev 10(2):207–229. doi:10.1007/s12015-013-9486-8

    Article  PubMed  CAS  Google Scholar 

  • Van Keymeulen A, Rocha AS, Ousset M, Beck B, Bouvencourt G, Rock J, Sharma N, Dekoninck S, Blanpain C (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479(7372):189–193. doi:10.1038/nature10573

    Article  PubMed  CAS  Google Scholar 

  • Visvader JE, Smith GH (2011) Murine mammary epithelial stem cells: discovery, function, and current status. Cold Spring Harb Perspect Biol 3(2). doi:10.1101/cshperspect.a004879

    Google Scholar 

  • Vlashi E, Pajonk F (2015) Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol 31:28–35. doi:10.1016/j.semcancer.2014.07.001

    Article  CAS  PubMed  Google Scholar 

  • Wagner KU, Schmidt JW (2011) The two faces of Janus kinases and their respective STATs in mammary gland development and cancer. J Carcinog 10:32. doi:10.4103/1477-3163.90677

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Walther V, Alison MR (2015) Cell lineage tracing in human epithelial tissues using mitochondrial DNA mutations as clonal markers. Wiley Interdiscip Rev Dev Biol. doi:10.1002/wdev.203

    PubMed  Google Scholar 

  • Wang C, Wang Y, McNutt MA, Zhu WG (2011) Autophagy process is associated with anti-neoplastic function. Acta Biochim Biophys Sin (Shanghai) 43(6):425–432. doi:10.1093/abbs/gmr028

    Article  CAS  Google Scholar 

  • Wang D, Cai C, Dong X, Yu QC, Zhang XO, Yang L, Zeng YA (2015) Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517(7532):81–84. doi:10.1038/nature13851

    Article  CAS  PubMed  Google Scholar 

  • Williams KE, Bundred NJ, Landberg G, Clarke RB, Farnie G (2015) Focal adhesion kinase and Wnt signaling regulate human ductal carcinoma in situ stem cell activity and response to radiotherapy. Stem Cells 33(2):327–341. doi:10.1002/stem.1843

    Article  PubMed  CAS  Google Scholar 

  • Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB (1998) The multifaceted roles of nitric oxide in cancer. Carcinogenesis 19(5):711–721

    Article  CAS  PubMed  Google Scholar 

  • **ng F, Okuda H, Watabe M, Kobayashi A, Pai SK, Liu W, Pandey PR, Fukuda K, Hirota S, Sugai T, Wakabayshi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Mo YY, Watabe K (2011) Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30(39):4075–4086. doi:10.1038/onc.2011.122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu J, Prosperi JR, Choudhury N, Olopade OI, Goss KH (2015) beta-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells. PLoS ONE 10(2):e0117097. doi:10.1371/journal.pone.0117097

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yamasaki K, Edington HD, McClosky C, Tzeng E, Lizonova A, Kovesdi I, Steed DL, Billiar TR (1998) Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J Clin Investig 101(5):967–971. doi:10.1172/JCI2067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin S, Xu L, Bonfil RD, Banerjee S, Sarkar FH, Sethi S, Reddy KB (2013) Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer. Mol Cancer Ther 12(4):491–498. doi:10.1158/1535-7163.MCT-12-1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Claerhout S, Prat A, Dobrolecki LE, Petrovic I, Lai Q, Landis MD, Wiechmann L, Schiff R, Giuliano M, Wong H, Fuqua SW, Contreras A, Gutierrez C, Huang J, Mao S, Pavlick AC, Froehlich AM, Wu MF, Tsimelzon A, Hilsenbeck SG, Chen ES, Zuloaga P, Shaw CA, Rimawi MF, Perou CM, Mills GB, Chang JC, Lewis MT (2013) A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. Cancer Res 73(15):4885–4897. doi:10.1158/0008-5472.CAN-12-4081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E 3rd, Zhang Y (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A 104(41):16158–16163. doi:10.1073/pnas.0702596104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu L, Cheng X, Ding Y, Shi J, ** H, Wang H, Wu Y, Ye J, Lu Y, Wang TC, Yang CS, Tu SP (2014) Bone marrow-derived myofibroblasts promote colon tumorigenesis through the IL-6/JAK2/STAT3 pathway. Cancer Lett 343(1):80–89. doi:10.1016/j.canlet.2013.09.017

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Houston Methodist Hospital, Houston Methodist Cancer Center, Houston, TX, 77030, USA

    Dong Soon Choi

  2. Weill Cornell Medical College, New York, NY, 10065, USA

    Roberto R. Rosato

  3. Department of Oncology, Houston Methodist Hospital, Houston Methodist Cancer Center, Houston, TX, 77030, USA

    Jenny C. Chang

Authors
  1. Dong Soon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto R. Rosato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jenny C. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jenny C. Chang .

Editor information

Editors and Affiliations

  1. Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Sunil Badve

  2. Indiana University School of Medicine, Dept of Pathology & Laboratory Medicine Indiana University School of Medicine, Indianapolis, Indiana, USA

    Yesim Gökmen-Polar

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Choi, D.S., Rosato, R.R., Chang, J.C. (2016). Breast Cancer Stem Cells. In: Badve, S., Gökmen-Polar, Y. (eds) Molecular Pathology of Breast Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-41761-5_10

Download citation

Publish with us

Policies and ethics

Search

Navigation