Breast Cancer Research and Treatment

, Volume 151, Issue 3, pp 491–500 | Cite as

Circulating tumor cell clusters-associated gene plakoglobin and breast cancer survival

  • Lingeng Lu
  • Hongmei Zeng
  • Xinsheng Gu
  • Wenxue Ma


Breast cancer recurrence is a major cause of the disease-specific death. Circulating tumor cells (CTCs) are negatively associated with breast cancer survival. Plakoglobin, a cell adhesion protein, was recently reported as a determinant of CTCs types, single or clustered ones. Here, we aim to summarize the studies on the roles of plakoglobin and evaluate the association of plakoglobin and breast cancer survival. Plakoglobin as a key component in both cell adhesion and the signaling pathways was briefly reviewed first. Then the double-edge functions of plakoglobin in tumors and its association with CTCs and breast cancer metastasis were introduced. Finally, based on an open-access database, the association between plakoglobin and breast cancer survival was investigated using univariate and multivariate survival analyses. Plakoglobin may be a molecule functioning as a double-edge sword. Loss of plakoglobin expression leads to increased motility of epithelial cells, thereby promoting epithelial–mesenchymal transition and further metastasis of cancer. However, studies also show that plakoglobin can function as an oncogene. High expression of plakoglobin results in clustered tumor cells in circulation with high metastatic potential in breast cancer and shortened patient survival. Plakoglobin may be a potential prognostic biomarker that can be exploited to develop as a therapeutic target for breast cancer.


Breast cancer metastasis Circulating tumor cells (CTCs) plakoglobin (Junction plakoglobin, JUP



The authors thank the research groups who provide online tool GOBO with the datasets to allow the analyses of gene expression and survival.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics. CA Cancer J Clin 65(1):5–29. doi: 10.3322/caac.21254 CrossRefPubMedGoogle Scholar
  2. 2.
    Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, Marubini E (2002) Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347(16):1227–1232. doi: 10.1056/NEJMoa020989 CrossRefPubMedGoogle Scholar
  3. 3.
    Blichert-Toft M, Nielsen M, During M, Moller S, Rank F, Overgaard M, Mouridsen HT (2008) Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol. Acta Oncol 47(4):672–681. doi: 10.1080/02841860801971439 CrossRefPubMedGoogle Scholar
  4. 4.
    Nielsen HM, Overgaard M, Grau C, Jensen AR, Overgaard J (2006) Loco-regional recurrence after mastectomy in high-risk breast cancer–risk and prognosis. An analysis of patients from the DBCG 82 b&c randomization trials. Radiother Oncol 79(2):147–155. doi: 10.1016/j.radonc.2006.04.006 CrossRefPubMedGoogle Scholar
  5. 5.
    Visvader JE, Lindeman GJ (2012) Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10(6):717–728. doi: 10.1016/j.stem.2012.05.007 CrossRefPubMedGoogle Scholar
  6. 6.
    El Helou R, Wicinski J, Guille A, Adelaide J, Finetti P, Bertucci F, Chaffanet M, Birnbaum D, Charafe-Jauffret E, Ginestier C (2014) Brief reports: a distinct DNA methylation signature defines breast cancer stem cells and predicts cancer outcome. Stem Cells 32(11):3031–3036. doi: 10.1002/stem.1792 CrossRefPubMedGoogle Scholar
  7. 7.
    Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802. doi: 10.1056/NEJMoa050434 CrossRefPubMedGoogle Scholar
  8. 8.
    Berman AT, Thukral AD, Hwang WT, Solin LJ, Vapiwala N (2013) Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment. Clin Breast Cancer 13(2):88–94. doi: 10.1016/j.clbc.2012.11.001 CrossRefPubMedGoogle Scholar
  9. 9.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621. doi: 10.1158/1078-0432.CCR-06-0169 CrossRefPubMedGoogle Scholar
  10. 10.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563. doi: 10.1038/nature06188 CrossRefPubMedGoogle Scholar
  11. 11.
    Kasai T, Chen L, Mizutani A, Kudoh T, Murakami H, Fu L, Seno M (2014) Cancer stem cells converted from pluripotent stem cells and the cancerous niche. J Stem Cells Regen Med 10(1):2–7PubMedCentralPubMedGoogle Scholar
  12. 12.
    Aggarwal C, Meropol NJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, Miller MC, Cohen SJ (2013) Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann Oncol 24(2):420–428. doi: 10.1093/annonc/mds336 CrossRefPubMedGoogle Scholar
  13. 13.
    Deneve E, Riethdorf S, Ramos J, Nocca D, Coffy A, Daures JP, Maudelonde T, Fabre JM, Pantel K, Alix-Panabieres C (2013) Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem 59(9):1384–1392. doi: 10.1373/clinchem.2013.202846 CrossRefPubMedGoogle Scholar
  14. 14.
    Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C (2012) Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 30(5):525–532. doi: 10.1200/JCO.2010.33.3716 CrossRefPubMedGoogle Scholar
  15. 15.
    Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, Blackhall FH (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563. doi: 10.1200/JCO.2010.28.7045 CrossRefPubMedGoogle Scholar
  16. 16.
    Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, Heller G (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10(3):233–239. doi: 10.1016/S1470-2045(08)70340-1 CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, Liu J, Pantel K (2012) Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res 18(20):5701–5710. doi: 10.1158/1078-0432.CCR-12-1587 CrossRefPubMedGoogle Scholar
  18. 18.
    Alix-Panabieres C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14(9):623–631. doi: 10.1038/nrc3820 CrossRefPubMedGoogle Scholar
  19. 19.
    Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, Holland-Letz T, Hofner T, Sprick M, Scharpff M, Marme F, Sinn HP, Pantel K, Weichert W, Trumpp A (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544. doi: 10.1038/nbt.2576 CrossRefPubMedGoogle Scholar
  20. 20.
    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122. doi: 10.1016/j.cell.2014.07.013 CrossRefPubMedGoogle Scholar
  21. 21.
    Krebs MG, Metcalf RL, Carter L, Brady G, Blackhall FH, Dive C (2014) Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol 11(3):129–144. doi: 10.1038/nrclinonc.2013.253 CrossRefPubMedGoogle Scholar
  22. 22.
    Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial–mesenchymal-like transition and promotes metastasis. Cancer Cell 20(5):576–590. doi: 10.1016/j.ccr.2011.09.009 CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584. doi: 10.1126/science.1228522 CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Wels J, Kaplan RN, Rafii S, Lyden D (2008) Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev 22(5):559–574. doi: 10.1101/gad.1636908 CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293. doi: 10.1038/nrc2621 CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Aktary Z, Pasdar M (2012) Plakoglobin: role in tumorigenesis and metastasis. Int J Cell Biol 2012:189521. doi: 10.1155/2012/189521 CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Todorovic V, Desai BV, Patterson MJ, Amargo EV, Dubash AD, Yin T, Jones JC, Green KJ (2010) Plakoglobin regulates cell motility through Rho- and fibronectin-dependent Src signaling. J Cell Sci 123(Pt 20):3576–3586. doi: 10.1242/jcs.070391 CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Shair KH, Schnegg CI, Raab-Traub N (2008) EBV latent membrane protein 1 effects on plakoglobin, cell growth, and migration. Cancer Res 68(17):6997–7005. doi: 10.1158/0008-5472.CAN-08-1178 CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Rieger-Christ KM, Ng L, Hanley RS, Durrani O, Ma H, Yee AS, Libertino JA, Summerhayes IC (2005) Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential. Br J Cancer 92(12):2153–2159. doi: 10.1038/sj.bjc.6602651 CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Yin T, Getsios S, Caldelari R, Kowalczyk AP, Muller EJ, Jones JC, Green KJ (2005) Plakoglobin suppresses keratinocyte motility through both cell-cell adhesion-dependent and -independent mechanisms. Proc Natl Acad Sci USA 102(15):5420–5425. doi: 10.1073/pnas.0501676102 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR, Fearon ER (2000) Gamma-catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes Dev 14(11):1319–1331PubMedCentralPubMedGoogle Scholar
  32. 32.
    Hakimelahi S, Parker HR, Gilchrist AJ, Barry M, Li Z, Bleackley RC, Pasdar M (2000) Plakoglobin regulates the expression of the anti-apoptotic protein BCL-2. J Biol Chem 275(15):10905–10911CrossRefPubMedGoogle Scholar
  33. 33.
    Shiina H, Breault JE, Basset WW, Enokida H, Urakami S, Li LC, Okino ST, Deguchi M, Kaneuchi M, Terashima M, Yoneda T, Shigeno K, Carroll PR, Igawa M, Dahiya R (2005) Functional loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer. Cancer Res 65(6):2130–2138. doi: 10.1158/0008-5472.CAN-04-3398 CrossRefPubMedGoogle Scholar
  34. 34.
    Cowin P, Kapprell HP, Franke WW, Tamkun J, Hynes RO (1986) Plakoglobin: a protein common to different kinds of intercellular adhering junctions. Cell 46(7):1063–1073CrossRefPubMedGoogle Scholar
  35. 35.
    Knudsen KA, Wheelock MJ (1992) Plakoglobin, or an 83-kD homologue distinct from beta-catenin, interacts with E-cadherin and N-cadherin. J Cell Biol 118(3):671–679CrossRefPubMedGoogle Scholar
  36. 36.
    Hu P, Berkowitz P, Madden VJ, Rubenstein DS (2006) Stabilization of plakoglobin and enhanced keratinocyte cell–cell adhesion by intracellular O-glycosylation. J Biol Chem 281(18):12786–12791. doi: 10.1074/jbc.M511702200 CrossRefPubMedGoogle Scholar
  37. 37.
    Fukunaga Y, Liu H, Shimizu M, Komiya S, Kawasuji M, Nagafuchi A (2005) Defining the roles of beta-catenin and plakoglobin in cell–cell adhesion: isolation of beta-catenin/plakoglobin-deficient F9 cells. Cell Struct Funct 30(2):25–34CrossRefPubMedGoogle Scholar
  38. 38.
    Lewalle JM, Bajou K, Desreux J, Mareel M, Dejana E, Noel A, Foidart JM (1997) Alteration of interendothelial adherens junctions following tumor cell–endothelial cell interaction in vitro. Exp Cell Res 237(2):347–356. doi: 10.1006/excr.1997.3799 CrossRefPubMedGoogle Scholar
  39. 39.
    Acehan D, Petzold C, Gumper I, Sabatini DD, Muller EJ, Cowin P, Stokes DL (2008) Plakoglobin is required for effective intermediate filament anchorage to desmosomes. J Invest Dermatol 128(11):2665–2675. doi: 10.1038/jid.2008.141 CrossRefPubMedGoogle Scholar
  40. 40.
    Palka HL, Green KJ (1997) Roles of plakoglobin end domains in desmosome assembly. J Cell Sci 110(Pt 19):2359–2371PubMedGoogle Scholar
  41. 41.
    Ruiz P, Brinkmann V, Ledermann B, Behrend M, Grund C, Thalhammer C, Vogel F, Birchmeier C, Gunthert U, Franke WW, Birchmeier W (1996) Targeted mutation of plakoglobin in mice reveals essential functions of desmosomes in the embryonic heart. J Cell Biol 135(1):215–225CrossRefPubMedGoogle Scholar
  42. 42.
    Kirchhof P, Fabritz L, Zwiener M, Witt H, Schafers M, Zellerhoff S, Paul M, Athai T, Hiller KH, Baba HA, Breithardt G, Ruiz P, Wichter T, Levkau B (2006) Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 114(17):1799–1806. doi: 10.1161/CIRCULATIONAHA.106.624502 CrossRefPubMedGoogle Scholar
  43. 43.
    Fabritz L, Hoogendijk MG, Scicluna BP, van Amersfoorth SC, Fortmueller L, Wolf S, Laakmann S, Kreienkamp N, Piccini I, Breithardt G, Noppinger PR, Witt H, Ebnet K, Wichter T, Levkau B, Franke WW, Pieperhoff S, de Bakker JM, Coronel R, Kirchhof P (2011) Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. J Am Coll Cardiol 57(6):740–750. doi: 10.1016/j.jacc.2010.09.046 CrossRefPubMedGoogle Scholar
  44. 44.
    Behrens J, Mareel MM, Van Roy FM, Birchmeier W (1989) Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell–cell adhesion. J Cell Biol 108(6):2435–2447CrossRefPubMedGoogle Scholar
  45. 45.
    Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66(1):107–119CrossRefPubMedGoogle Scholar
  46. 46.
    Kundu ST, Gosavi P, Khapare N, Patel R, Hosing AS, Maru GB, Ingle A, Decaprio JA, Dalal SN (2008) Plakophilin3 downregulation leads to a decrease in cell adhesion and promotes metastasis. Int J Cancer 123(10):2303–2314. doi: 10.1002/ijc.23797 CrossRefPubMedGoogle Scholar
  47. 47.
    Gosavi P, Kundu ST, Khapare N, Sehgal L, Karkhanis MS, Dalal SN (2011) E-cadherin and plakoglobin recruit plakophilin3 to the cell border to initiate desmosome assembly. Cell Mol Life Sci 68(8):1439–1454. doi: 10.1007/s00018-010-0531-3 CrossRefPubMedGoogle Scholar
  48. 48.
    Parker HR, Li Z, Sheinin H, Lauzon G, Pasdar M (1998) Plakoglobin induces desmosome formation and epidermoid phenotype in N-cadherin-expressing squamous carcinoma cells deficient in plakoglobin and E-cadherin. Cell Motil Cytoskeleton 40(1):87–100. doi: 10.1002/(SICI)1097-0169(1998)40:1<87:AID-CM8>3.0.CO;2-C CrossRefPubMedGoogle Scholar
  49. 49.
    Li Z, Gallin WJ, Lauzon G, Pasdar M (1998) L-CAM expression induces fibroblast-epidermoid transition in squamous carcinoma cells and down-regulates the endogenous N-cadherin. J Cell Sci 111(Pt 7):1005–1019PubMedGoogle Scholar
  50. 50.
    Franzen CA, Todorovic V, Desai BV, Mirzoeva S, Yang XJ, Green KJ, Pelling JC (2012) The desmosomal armadillo protein plakoglobin regulates prostate cancer cell adhesion and motility through vitronectin-dependent Src signaling. PLoS ONE 7(7):e42132. doi: 10.1371/journal.pone.0042132 CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Tiwari I, Yoon MH, Park BJ, Jang KL (2015) Hepatitis C virus core induces epithelial–mesenchymal transition in human hepatocytes by upregulating E12/E47 levels. Cancer Lett. doi: 10.1016/j.canlet.2015.03.032 PubMedGoogle Scholar
  52. 52.
    Zhurinsky J, Shtutman M, Ben-Ze’ev A (2000) Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. J Cell Sci 113(Pt 18):3127–3139PubMedGoogle Scholar
  53. 53.
    Karnovsky A, Klymkowsky MW (1995) Anterior axis duplication in Xenopus induced by the over-expression of the cadherin-binding protein plakoglobin. Proc Natl Acad Sci USA 92(10):4522–4526CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Bradley RS, Cowin P, Brown AM (1993) Expression of Wnt-1 in PC12 cells results in modulation of plakoglobin and E-cadherin and increased cellular adhesion. J Cell Biol 123(6 Pt 2):1857–1865CrossRefPubMedGoogle Scholar
  55. 55.
    Martin ED, Moriarty MA, Byrnes L, Grealy M (2009) Plakoglobin has both structural and signalling roles in zebrafish development. Dev Biol 327(1):83–96. doi: 10.1016/j.ydbio.2008.11.036 CrossRefPubMedGoogle Scholar
  56. 56.
    Spindler V, Dehner C, Hubner S, Waschke J (2014) Plakoglobin but not desmoplakin regulates keratinocyte cohesion via modulation of p38MAPK signaling. J Invest Dermatol 134(6):1655–1664. doi: 10.1038/jid.2014.21 CrossRefPubMedGoogle Scholar
  57. 57.
    Mao X, Li H, Sano Y, Gaestel M, Mo Park J, Payne AS (2014) MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol 134(1):68–76. doi: 10.1038/jid.2013.224 CrossRefPubMedGoogle Scholar
  58. 58.
    Berkowitz P, Hu P, Liu Z, Diaz LA, Enghild JJ, Chua MP, Rubenstein DS (2005) Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem 280(25):23778–23784. doi: 10.1074/jbc.M501365200 CrossRefPubMedGoogle Scholar
  59. 59.
    Tokonzaba E, Chen J, Cheng X, Den Z, Ganeshan R, Muller EJ, Koch PJ (2013) Plakoglobin as a regulator of desmocollin gene expression. J Invest Dermatol 133(12):2732–2740. doi: 10.1038/jid.2013.220 CrossRefPubMedGoogle Scholar
  60. 60.
    Hoverter NP, Waterman ML (2008) A Wnt-fall for gene regulation: repression. Sci Signal 1(39):pe43. doi: 10.1126/scisignal.139pe43 CrossRefPubMedGoogle Scholar
  61. 61.
    Pan H, Gao F, Papageorgis P, Abdolmaleky HM, Faller DV, Thiagalingam S (2007) Aberrant activation of gamma-catenin promotes genomic instability and oncogenic effects during tumor progression. Cancer Biol Ther 6(10):1638–1643CrossRefPubMedGoogle Scholar
  62. 62.
    Aktary Z, Pasdar M (2013) Plakoglobin represses SATB1 expression and decreases in vitro proliferation, migration and invasion. PLoS ONE 8(11):e78388. doi: 10.1371/journal.pone.0078388 CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Cohen S, Lee D, Zhai B, Gygi SP, Goldberg AL (2014) Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation. J Cell Biol 204(5):747–758. doi: 10.1083/jcb.201304167 CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Chen YJ, Lee LY, Chao YK, Chang JT, Lu YC, Li HF, Chiu CC, Li YC, Li YL, Chiou JF, Cheng AJ (2013) DSG3 facilitates cancer cell growth and invasion through the DSG3-plakoglobin-TCF/LEF-Myc/cyclin D1/MMP signaling pathway. PLoS ONE 8(5):e64088. doi: 10.1371/journal.pone.0064088 CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Lai YH, Cheng J, Cheng D, Feasel ME, Beste KD, Peng J, Nusrat A, Moreno CS (2011) SOX4 interacts with plakoglobin in a Wnt3a-dependent manner in prostate cancer cells. BMC Cell Biol 12:50. doi: 10.1186/1471-2121-12-50 CrossRefPubMedCentralPubMedGoogle Scholar
  66. 66.
    Mathenge EG, Dean CA, Clements D, Vaghar-Kashani A, Photopoulos S, Coyle KM, Giacomantonio M, Malueth B, Nunokawa A, Jordan J, Lewis JD, Gujar SA, Marcato P, Lee PW, Giacomantonio CA (2014) Core needle biopsy of breast cancer tumors increases distant metastases in a mouse model. Neoplasia 16(11):950–960. doi: 10.1016/j.neo.2014.09.004 CrossRefPubMedCentralPubMedGoogle Scholar
  67. 67.
    Song GD, Sun Y, Shen H, Li W (2015) SOX4 overexpression is a novel biomarker of malignant status and poor prognosis in breast cancer patients. Tumour Biol. doi: 10.1007/s13277-015-3051-9 Google Scholar
  68. 68.
    Aktary Z, Kulak S, Mackey J, Jahroudi N, Pasdar M (2013) Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3sigma. J Cell Sci 126(Pt 14):3031–3042. doi: 10.1242/jcs.120642 CrossRefPubMedGoogle Scholar
  69. 69.
    Aberle H, Bierkamp C, Torchard D, Serova O, Wagner T, Natt E, Wirsching J, Heidkamper C, Montagna M, Lynch HT et al (1995) The human plakoglobin gene localizes on chromosome 17q21 and is subjected to loss of heterozygosity in breast and ovarian cancers. Proc Natl Acad Sci USA 92(14):6384–6388CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    McPherson K, Steel CM, Dixon JM (2000) ABC of breast diseases. Breast cancer-epidemiology, risk factors, and genetics. BMJ 321(7261):624–628CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Boersma BJ, Reimers M, Yi M, Ludwig JA, Luke BT, Stephens RM, Yfantis HG, Lee DH, Weinstein JN, Ambs S (2008) A stromal gene signature associated with inflammatory breast cancer. Int J Cancer 122(6):1324–1332. doi: 10.1002/ijc.23237 CrossRefPubMedGoogle Scholar
  72. 72.
    Korde LA, Lusa L, McShane L, Lebowitz PF, Lukes L, Camphausen K, Parker JS, Swain SM, Hunter K, Zujewski JA (2010) Gene expression pathway analysis to predict response to neoadjuvant docetaxel and capecitabine for breast cancer. Breast Cancer Res Treat 119(3):685–699. doi: 10.1007/s10549-009-0651-3 CrossRefPubMedGoogle Scholar
  73. 73.
    Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO (1994) Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 125(2):437–446CrossRefPubMedGoogle Scholar
  74. 74.
    Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, Gires O (2009) Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11(2):162–171. doi: 10.1038/ncb1824 CrossRefPubMedGoogle Scholar
  75. 75.
    Galoian K, Qureshi A, Wideroff G, Temple HT (2015) Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells. Mol Clin Oncol 3(1):171–178. doi: 10.3892/mco.2014.445 PubMedCentralPubMedGoogle Scholar
  76. 76.
    Woelfle U, Cloos J, Sauter G, Riethdorf L, Janicke F, van Diest P, Brakenhoff R, Pantel K (2003) Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 63(18):5679–5684PubMedGoogle Scholar
  77. 77.
    Bailey CK, Mittal MK, Misra S, Chaudhuri G (2012) High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG. J Biol Chem 287(23):19472–19486. doi: 10.1074/jbc.M112.345728 CrossRefPubMedCentralPubMedGoogle Scholar
  78. 78.
    Shafiei F, Rahnama F, Pawella L, Mitchell MD, Gluckman PD, Lobie PE (2008) DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells. Oncogene 27(18):2602–2612. doi: 10.1038/sj.onc.1210917 CrossRefPubMedGoogle Scholar
  79. 79.
    Stajduhar E, Sedic M, Lenicek T, Radulovic P, Kerenji A, Kruslin B, Pavelic K, Kraljevic Pavelic S (2014) Expression of growth hormone receptor, plakoglobin and NEDD9 protein in association with tumour progression and metastasis in human breast cancer. Tumour Biol 35(7):6425–6434. doi: 10.1007/s13277-014-1827-y CrossRefPubMedGoogle Scholar
  80. 80.
    Holen I, Whitworth J, Nutter F, Evans A, Brown HK, Lefley DV, Barbaric I, Jones M, Ottewell PD (2012) Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo. Breast Cancer Res 14(3):R86. doi: 10.1186/bcr3201 CrossRefPubMedCentralPubMedGoogle Scholar
  81. 81.
    Storci G, Sansone P, Trere D, Tavolari S, Taffurelli M, Ceccarelli C, Guarnieri T, Paterini P, Pariali M, Montanaro L, Santini D, Chieco P, Bonafe M (2008) The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol 214(1):25–37. doi: 10.1002/path.2254 CrossRefPubMedGoogle Scholar
  82. 82.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767. doi: 10.1172/JCI45014 CrossRefPubMedCentralPubMedGoogle Scholar
  83. 83.
    Alves CC, Carneiro F, Hoefler H, Becker KF (2009) Role of the epithelial–mesenchymal transition regulator Slug in primary human cancers. Front Biosci (Landmark Ed) 14:3035–3050CrossRefGoogle Scholar
  84. 84.
    Shirley SH, Hudson LG, He J, Kusewitt DF (2010) The skinny on Slug. Mol Carcinog 49(10):851–861. doi: 10.1002/mc.20674 CrossRefPubMedCentralPubMedGoogle Scholar
  85. 85.
    Mittal MK, Myers JN, Misra S, Bailey CK, Chaudhuri G (2008) In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells. Biochem Biophys Res Commun 372(1):30–34. doi: 10.1016/j.bbrc.2008.04.187 CrossRefPubMedCentralPubMedGoogle Scholar
  86. 86.
    Mittal MK, Singh K, Misra S, Chaudhuri G (2011) SLUG-induced elevation of D1 cyclin in breast cancer cells through the inhibition of its ubiquitination. J Biol Chem 286(1):469–479. doi: 10.1074/jbc.M110.164384 CrossRefPubMedCentralPubMedGoogle Scholar
  87. 87.
    Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564. doi: 10.1126/science.1203543 CrossRefPubMedGoogle Scholar
  88. 88.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572. doi: 10.1038/nrc865 CrossRefPubMedGoogle Scholar
  89. 89.
    Plaks V, Koopman CD, Werb Z (2013) Cancer. Circulating tumor cells. Science 341(6151):1186–1188. doi: 10.1126/science.1235226 CrossRefPubMedGoogle Scholar
  90. 90.
    Labelle M, Begum S, Hynes RO (2014) Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci USA 111(30):E3053–E3061. doi: 10.1073/pnas.1411082111 CrossRefPubMedCentralPubMedGoogle Scholar
  91. 91.
    Ringner M, Fredlund E, Hakkinen J, Borg A, Staaf J (2011) GOBO: gene expression-based outcome for breast cancer online. PLoS ONE 6(3):e17911. doi: 10.1371/journal.pone.0017911 CrossRefPubMedCentralPubMedGoogle Scholar
  92. 92.
    Fredlund E, Staaf J, Rantala JK, Kallioniemi O, Borg A, Ringner M (2012) The gene expression landscape of breast cancer is shaped by tumor protein p53 status and epithelial–mesenchymal transition. Breast Cancer Res 14(4):R113. doi: 10.1186/bcr3236 CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lingeng Lu
    • 1
  • Hongmei Zeng
    • 2
  • Xinsheng Gu
    • 3
  • Wenxue Ma
    • 4
    • 5
  1. 1.Department of Chronic Disease Epidemiology, School of Public Health, School of Medicine, Yale Cancer CenterYale UniversityNew HavenUSA
  2. 2.National Office for Cancer Prevention and Control, Cancer HospitalChinese Academy of Medical Sciences/National Cancer CenterBeijingChina
  3. 3.Department of PharmacologyHubei University of MedicineShiyanChina
  4. 4.Moores Cancer CenterUniversity of California San DiegoLa JollaUSA
  5. 5.Cynvenio Biosystems Inc.Westlake VillageUSA

Personalised recommendations