Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches

Abstract

Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K→AKT and mitogen-activated protein kinase kinase (MEK)→extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/β-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-κB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Kufe D . Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 2009; 9: 874–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kufe D, Inghirami G, Abe M, Hayes D, Justi-Wheeler H, Schlom J . Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. Hybridoma 1984; 3: 223–232.

    Article  CAS  PubMed  Google Scholar 

  3. Ligtenberg MJ, Kruijshaar L, Buijs F, van Meijer M, Litvinov SV, Hilkens J . Cell-associated episialin is a complex containing two proteins derived from a common precursor. J Biol Chem 1992; 267: 6171–6177.

    Article  CAS  PubMed  Google Scholar 

  4. Levitin F, Stern O, Weiss M, Gil-Henn C, Ziv R, Prokocimer Z et al. The MUC1 SEA module is a self-cleaving domain. J Biol Chem 2005; 280: 33374–33386.

    Article  CAS  PubMed  Google Scholar 

  5. Macao B, Johansson DG, Hansson GC, Hard T . Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin. Nat Struct Mol Biol 2006; 13: 71–76.

    Article  CAS  PubMed  Google Scholar 

  6. Siddiqui J, Abe M, Hayes D, Shani E, Yunis E, Kufe D . Isolation and sequencing of a cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc Natl Acad Sci USA 1988; 85: 2320–2323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gendler S, Taylor-Papadimitriou J, Duhig T, Rothbard J, Burchell JA . A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats. J Biol Chem 1988; 263: 12820–12823.

    Article  CAS  PubMed  Google Scholar 

  8. Abe M, Kufe D . Structural analysis of the DF3 human breast carcinoma associated protein. Cancer Res 1989; 49: 2834–2839.

    CAS  PubMed  Google Scholar 

  9. Hayes DF, Sekine H, Ohno T, Abe M, Keefe K, Kufe DW . Use of a murine monoclonal antibody for detection of circulating DF3 antigen levels in breast cancer patients. J Clin Invest 1985; 75: 1671–1678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rakha EA, Boyce RW, Abd El-Rehim D, Kurien T, Green AR, Paish EC et al. Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol 2005; 18: 1295–1304.

    Article  CAS  PubMed  Google Scholar 

  11. Rahn JJ, Dabbagh L, Pasdar M, Hugh JC . The importance of MUC1 cellular localization in patients with breast carcinoma: an immunohistologic study of 71 patients and review of the literature. Cancer 2001; 91: 1973–1982.

    Article  CAS  PubMed  Google Scholar 

  12. McGuckin MA, Walsh MD, Hohn BG, Ward BG, Wright RG . Prognostic significance of MUC1 epithelial mucin expression in breast cancer. Hum Pathol 1995; 26: 432–439.

    Article  CAS  PubMed  Google Scholar 

  13. Merlo G, Siddiqui J, Cropp C, Liscia DS, Lidereau R, Callahan R et al. DF3 tumor-associated antigen gene is located in a region on chromosome 1q frequently altered in primary human breast cancer. Cancer Res 1989; 49: 6966–6971.

    CAS  PubMed  Google Scholar 

  14. Bieche I, Lidereau R . A gene dosage effect is responsible for high overexpression of the MUC1 gene observed in human breast tumors. Cancer Genet Cytogenet 1997; 98: 75–80.

    Article  CAS  PubMed  Google Scholar 

  15. Lacunza E, Baudis M, Colussi AG, Segal-Eiras A, Croce MV, Abba MC . MUC1 oncogene amplification correlates with protein overexpression in invasive breast carcinoma cells. Cancer Genet Cytogenet 2010; 201: 102–110.

    Article  CAS  PubMed  Google Scholar 

  16. Abe M, Kufe D . Transcriptional regulation of the DF3 gene expression in human MCF-7 breast carcinoma cells. J Cell Physiol 1990; 143: 226–231.

    Article  CAS  PubMed  Google Scholar 

  17. Abe M, Kufe D . Characterization of cis-acting elements regulating transcription of the human DF3 breast carcinoma-associated antigen (MUC1) gene. Proc Natl Acad Sci USA 1993; 90: 282–286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kovarik A, Peat N, Wilson D, Gendler S, Taylor-Papadimitriou J . Analysis of the tissue-specific promoter of the MUC1 gene. J Biol Chem 1993; 268: 9917–9926.

    Article  CAS  PubMed  Google Scholar 

  19. Khodarev N, Ahmad R, Rajabi H, Pitroda S, Kufe T, McClary C et al. Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene 2010; 29: 920–929.

    Article  CAS  PubMed  Google Scholar 

  20. Ahmad R, Raina D, Joshi MD, Kawano T, Kharbanda S, Kufe D . MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res 2009; 69: 7013–7021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ahmad R, Rajabi H, Kosugi M, Joshi M, Alam M, Vasir B et al. MUC1-C oncoprotein promotes STAT3 activation in an auto-inductive regulatory loop. Sci Signal 2011; 4: ra9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Rajabi H, Jin C, Ahmad R, McClary C, Kufe D . Mucin 1 oncoprotein expression is suppressed by the miR-125b oncomir. Genes & Cancer 2010; 1: 62–65.

    Article  CAS  Google Scholar 

  23. Sachdeva M, Mo YY . MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res 2010; 70: 378–387.

    Article  CAS  PubMed  Google Scholar 

  24. Jin C, Rajabi H, Kufe D . miR-1226 targets expression of the mucin 1 oncoprotein and induces cell death. Int J Oncol 2010; 37: 61–69.

    CAS  PubMed  Google Scholar 

  25. Higgins MJ, Baselga J . Targeted therapies for breast cancer. J Clin Invest 2011; 121: 3797–3803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kufe D . Functional targeting of the MUC1 oncogene in human cancers. Cancer Biol Ther 2009; 8: 1201–1207.

    Article  Google Scholar 

  27. Khodarev N, Pitroda S, Beckett M, MacDermed D, Huang L, Kufe D et al. MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. Cancer Res 2009; 69: 2833–2837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pitroda S, Khodarev N, Beckett M, Kufe D, Weichselbaum R . MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment. Proc Natl Acad Sci USA 2009; 106: 5837–5841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He C, Hobert M, Friend L, Carlin C . The epidermal growth factor receptor juxtamembrane domain has multiple basolateral plasma membrane localization determinants, including a dominant signal with a polyproline core. J Biol Chem 2002; 277: 38284–38293.

    Article  CAS  PubMed  Google Scholar 

  30. Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 2003; 422: 322–326.

    Article  CAS  PubMed  Google Scholar 

  31. Ramasamy S, Duraisamy S, Barbashov S, Kawano T, Kharbanda S, Kufe D . The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Mol Cell 2007; 27: 992–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li Y, Ren J, Yu W, Li G, Kuwahara H, Yin L et al. The EGF receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and β-catenin. J Biol Chem 2001; 276: 35239–35242.

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Kuwahara H, Ren J, Wen G, Kufe D . The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3β and β-catenin. J Biol Chem 2001; 276: 6061–6064.

    Article  CAS  PubMed  Google Scholar 

  34. Schroeder J, Thompson M, Gardner M, Gendler S . Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J Biol Chem 2001; 276: 13057–13064.

    Article  CAS  PubMed  Google Scholar 

  35. Schroeder JA, Masri AA, Adriance MC, Tessier JC, Kotlarczyk KL, Thompson MC et al. MUC1 overexpression results in mammary gland tumorigenesis and prolonged alveolar differentiation. Oncogene 2004; 23: 5739–5747.

    Article  CAS  PubMed  Google Scholar 

  36. Pochampalli MR, Bitler BG, Schroeder JA . Transforming growth factor {alpha} dependent cancer progression is modulated by MUC1. Cancer Res 2007; 67: 6591–6598.

    Article  CAS  PubMed  Google Scholar 

  37. Merlin J, Stechly L, de Beauce S, Monte D, Leteurtre E, van Seuningen I et al. Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells. Oncogene 2011; 30: 2514–2525.

    Article  CAS  PubMed  Google Scholar 

  38. Raina D, Kosugi M, Ahmad R, Panchamoorthy G, Rajabi H, Alam M et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther 2011; 10: 806–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bitler BG, Goverdhan A, Schroeder JA . MUC1 regulates nuclear localization and function of the epidermal growth factor receptor. J Cell Sci 2010; 123: 1716–1723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li Y, Yu W-H, Ren J, Huang L, Kharbanda S, Loda M et al. Heregulin targets γ-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 protein. Mol Cancer Res 2003; 1: 765–775.

    CAS  PubMed  Google Scholar 

  41. Ren J, Raina D, Chen W, Li G, Huang L, Kufe D . MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling. Mol Cancer Res 2006; 4: 873–883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Singh PK, Behrens ME, Eggers JP, Cerny RL, Bailey JM, Shanmugam K et al. Phosphorylation of MUC1 by Met modulates interaction with p53 and MMP1 expression. J Biol Chem 2008; 283: 26985–26995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Singh PK, Wen Y, Swanson BJ, Shanmugam K, Kazlauskas A, Cerny RL et al. Platelet-derived growth factor receptor beta-mediated phosphorylation of MUC1 enhances invasiveness in pancreatic adenocarcinoma cells. Cancer Res 2007; 67: 5201–5210.

    Article  CAS  PubMed  Google Scholar 

  44. Engelman JA . Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009; 9: 550–562.

    Article  CAS  PubMed  Google Scholar 

  45. Liu P, Cheng H, Roberts TM, Zhao JJ . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8: 627–644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Raina D, Kharbanda S, Kufe D . The MUC1 oncoprotein activates the anti-apoptotic PI3K/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem 2004; 279: 20607–20612.

    Article  CAS  PubMed  Google Scholar 

  47. Horn G, Gaziel A, Wreschner DH, Smorodinsky NI, Ehrlich M . ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumor cells induced by truncated MUC1. Exp Cell Res 2009; 315: 1490–1504.

    Article  CAS  PubMed  Google Scholar 

  48. Kato K, Lu W, Kai H, Kim KC . Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling. Am J Physiol Lung Cell Mol Physiol 2007; 293: L686–L692.

    Article  CAS  PubMed  Google Scholar 

  49. Kosugi M, Ahmad R, Alam M, Uchida Y, Kufe D . MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS One 2011; 6: e28234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yao M, Zhang W, Zhang Q, Xing L, Xu A, Liu Q et al. Overexpression of MUC1 enhances proangiogenic activity of non-small-cell lung cancer cells through activation of Akt and extracellular signal-regulated kinase pathways. Lung 2011; 189: 453–460.

    Article  CAS  PubMed  Google Scholar 

  51. Woo JK, Choi Y, Oh S-H, Jeong J-H, Choi D-H, Seo H-S et al. Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway. Oncogene 2012; 31: 2187–2198.

    Article  CAS  PubMed  Google Scholar 

  52. Pandey P, Kharbanda S, Kufe D . Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein. Cancer Res 1995; 55: 4000–4003.

    CAS  PubMed  Google Scholar 

  53. Meerzaman D, Shapiro PS, Kim KC . Involvement of the MAP kinase ERK2 in MUC1 mucin signaling. Am J Physiol Lung Cell Mol Physiol 2001; 281: L86–L91.

    Article  CAS  PubMed  Google Scholar 

  54. Kinlough CL, Poland PA, Bruns JB, Harkleroad KL, Hughey RP . MUC1 membrane trafficking is modulated by multiple interactions. J Biol Chem 2004; 279: 53071–53077.

    Article  CAS  PubMed  Google Scholar 

  55. Kinlough CL, McMahan RJ, Poland PA, Bruns JB, Harkleroad KL, Stremple RJ et al. Recycling of MUC1 is dependent on its palmitoylation. J Biol Chem 2006; 281: 12112–12122.

    Article  CAS  PubMed  Google Scholar 

  56. Liao HJ, Carpenter G . Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol Biol Cell 2007; 18: 1064–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Leng Y, Cao C, Ren J, Huang L, Chen D, Ito M et al. Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J Biol Chem 2007; 282: 19321–19330.

    Article  CAS  PubMed  Google Scholar 

  58. Raina D, Ahmad R, Rajabi H, Panchamoorthy G, Kharbanda S, Kufe D . Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J Oncol 2012; 40: 1643–1649.

    CAS  PubMed  Google Scholar 

  59. Ren J, Agata N, Chen D, Li Y, Yu W-H, Huang L et al. Human MUC1 carcinoma-associated protein confers resistance to genotoxic anti-cancer agents. Cancer Cell 2004; 5: 163–175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D . MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 2006; 25: 20–31.

    Article  CAS  PubMed  Google Scholar 

  61. Polakis P . The many ways of Wnt in cancer. Curr Opin Genet Dev 2007; 17: 45–51.

    Article  CAS  PubMed  Google Scholar 

  62. Yamamoto M, Bharti A, Li Y, Kufe D . Interaction of the DF3/MUC1 breast carcinoma-associated antigen and β-catenin in cell adhesion. J Biol Chem 1997; 272: 12492–12494.

    Article  CAS  PubMed  Google Scholar 

  63. Li Y, Bharti A, Chen D, Gong J, Kufe D . Interaction of glycogen synthase kinase 3β with the DF3/MUC1 carcinoma-associated antigen and β-catenin. Mol Cell Biol 1998; 18: 7216–7224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ren J, Li Y, Kufe D . Protein kinase C δ regulates function of the DF3/MUC1 carcinoma antigen in β-catenin signaling. J Biol Chem 2002; 277: 17616–17622.

    Article  CAS  PubMed  Google Scholar 

  65. Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ . MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene 2003; 22: 1324–1332.

    Article  CAS  PubMed  Google Scholar 

  66. Li Y, Liu D, Chen D, Kharbanda S, Kufe D . Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003; 22: 6107–6110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wen Y, Caffrey T, Wheelock M, Johnson K, Hollingsworth M . Nuclear association of the cytoplasmic tail of MUC1 and β-catenin. J Biol Chem 2003; 278: 38029–38039.

    Article  CAS  PubMed  Google Scholar 

  68. Huang L, Ren J, Chen D, Li Y, Kharbanda S, Kufe D . MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther 2003; 2: 702–706.

    CAS  PubMed  Google Scholar 

  69. Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D . MUC1 oncoprotein blocks GSK3β-mediated phosphorylation and degradation of β-catenin. Cancer Res 2005; 65: 10413–10422.

    Article  CAS  PubMed  Google Scholar 

  70. Li Y, Yi H, Yao Y, Liao X, Xie Y, Yang J et al. The cytoplasmic domain of MUC1 induces hyperplasia in the mammary gland and correlates with nuclear accumulation of beta-catenin. PLoS One 2011; 6: e19102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hoppler S, Kavanagh CL . Wnt signalling: variety at the core. J Cell Sci 2007; 120: 385–393.

    Article  CAS  PubMed  Google Scholar 

  72. MacDonald BT, Tamai K, He X . Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17: 9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rajabi H, Ahmad R, Jin C, Kosugi M, Alam M, Joshi M et al. MUC1-C Oncoprotein Induces TCF7L2 activation and promotes cyclin D1 expression in human breast cancer cells. J Biol Chem 2012. 10703–10713.

  74. Hatsell S, Rowlands T, Hiremath M, Cowin P . Beta-catenin and Tcfs in mammary development and cancer. J Mammary Gland Biol Neoplasia 2003; 8: 145–158.

    Article  PubMed  Google Scholar 

  75. Yu Q, Geng Y, Sicinski P . Specific protection against breast cancers by cyclin D1 ablation. Nature 2001; 411: 1017–1021.

    Article  CAS  PubMed  Google Scholar 

  76. Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW . Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006; 9: 13–22.

    Article  CAS  PubMed  Google Scholar 

  77. Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett 1995; 90: 43–50.

    Article  CAS  PubMed  Google Scholar 

  78. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J . Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 1994; 57: 353–361.

    Article  CAS  PubMed  Google Scholar 

  79. Gillett C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C et al. Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 1994; 54: 1812–1817.

    CAS  PubMed  Google Scholar 

  80. McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD et al. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 1995; 11: 885–891.

    CAS  PubMed  Google Scholar 

  81. Lamb J, Ramaswamy S, Ford HL, Contreras B, Martinez RV, Kittrell FS et al. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 2003; 114: 323–334.

    Article  CAS  PubMed  Google Scholar 

  82. Udhayakumar G, Jayanthi V, Devaraj N, Devaraj H . Interaction of MUC1 with beta-catenin modulates the Wnt target gene cyclinD1 in H. pylori-induced gastric cancer. Mol Carcinog 2007; 46: 807–817.

    Article  CAS  PubMed  Google Scholar 

  83. Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yu H, Jove R . The STATs of cancer—new molecular targets come of age. Nat Rev Cancer 2004; 4: 97–105.

    Article  CAS  PubMed  Google Scholar 

  85. Lagow EL, Carson DD . Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-gamma and tumor necrosis factor-alpha. J Cell Biochem 2002; 86: 759–772.

    Article  CAS  PubMed  Google Scholar 

  86. Gaemers IC, Vos HL, Volders HH, van der Valk SW, Hilkens JA . STAT-responsive element in the promoter of the episialin/MUC1 gene is involved in its overexpression in carcinoma cells. J Biol Chem 2001; 276: 6191–6199.

    Article  CAS  PubMed  Google Scholar 

  87. Kondo S, Yoshizaki T, Wakisaka N, Horikawa T, Murono S, Jang KL et al. MUC1 induced by Epstein-Barr virus latent membrane protein 1 causes dissociation of the cell-matrix interaction and cellular invasiveness via STAT signaling. J Virol 2007; 81: 1554–1562.

    Article  CAS  PubMed  Google Scholar 

  88. Hayden MS, Ghosh S . Shared principles in NF-κB signaling. Cell 2008; 132: 344–362.

    Article  CAS  PubMed  Google Scholar 

  89. Thompson EJ, Shanmugam K, Hattrup CL, Kotlarczyk KL, Gutierrez A, Bradley JM et al. Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways. Mol Cancer Res 2006; 4: 489–497.

    Article  CAS  PubMed  Google Scholar 

  90. Ahmad R, Raina D, Trivedi V, Ren J, Rajabi H, Kharbanda S et al. MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signaling. Nat Cell Biol 2007; 9: 1419–1427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zaretsky JZ, Barnea I, Aylon Y, Gorivodsky M, Wreschner DH, Keydar I . MUC1 gene overexpressed in breast cancer: structure and transcriptional activity of the MUC1 promoter and role of estrogen receptor alpha (ERalpha) in regulation of the MUC1 gene expression. Mol Cancer 2006; 5: 57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Wei X, Xu H, Kufe D . MUC1 oncoprotein stabilizes and activates estrogen receptor α. Mol Cell 2006; 21: 295–305.

    Article  CAS  PubMed  Google Scholar 

  93. Pegram MD, Borges VF, Ibrahim N, Fuloria J, Shapiro C, Perez S et al. Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer. Breast Cancer Res 2009; 11: R73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Ibrahim NK, Yariz KO, Bondarenko I, Manikhas A, Semiglazov V, Alyasova A et al. Randomized phase II trial of letrozole plus anti-MUC1 antibody AS1402 in hormone receptor-positive locally advanced or metastatic breast cancer. Clin Cancer Res 2011; 17: 6822–6830.

    Article  CAS  PubMed  Google Scholar 

  95. Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ et al. Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res 2008; 14: 3060–3069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C et al. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clin Cancer Res 2011; 17: 7164–7173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Arlen PM, Pazdur M, Skarupa L, Rauckhorst M . Gulley JL. A randomized phase II study of docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in patients with metastatic breast cancer (NCI 05-C-0229). Clin Breast Cancer 2006; 7: 176–179.

    Article  CAS  PubMed  Google Scholar 

  98. Mohebtash M, Madan R, Gulley J, Jones J, Pazdur O, Heath M et al. Vaccine alone or with chemotherapy in patients with metastatic breast cancer (mBC). Am Soc Clin Oncol Breast Cancer Symp 2008, Abstract No: 163.

  99. Gulley J, Heery C, Bilusic M, Kim J, Stadler W, DiPaola R et al. Combining vaccines with other therapeutics: a strategy to accelerate proof of concept studies? Soc Immunother Cancer 2011, Oral Presentation Abstracts, p. 56.

  100. Raina D, Ahmad R, Joshi M, Yin L, Wu Z, Kawano T et al. Direct targeting of the MUC1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res 2009; 69: 5133–5141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhou J, Rajabi H, Kufe D . MUC1-C oncoprotein is a target for small molecule inhibitors. Mol Pharm 2011; 79: 886–893.

    Article  CAS  Google Scholar 

  102. Joshi MD, Ahmad R, Raina D, Rajabi H, Bubley G, Kharbanda S et al. MUC1 oncoprotein is a druggable target in human prostate cancer cells. Mol Cancer Ther 2009; 8: 3056–3065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rajabi H, Ahmad R, Jin C, Joshi MD, Guha M, Alam M et al. MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells. Prostate 2012; 72: 1659–1668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by Grant CA97098 awarded by the National Cancer Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D W Kufe.

Ethics declarations

Competing interests

Dr Kufe has ownership interest in Genus Oncology and is a consultant to the company.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kufe, D. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 32, 1073–1081 (2013). https://doi.org/10.1038/onc.2012.158

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.158

Keywords

This article is cited by

Search

Quick links