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Upregulation of Trop-2 quantitatively stimulates human cancer growth


Trop-2 is a calcium signal transducer that is associated with transformed cell growth in experimental systems. However, its role in human cancer remains essentially unknown. In this study, we profiled Trop-2 expression in normal human tissues at the mRNA and protein levels. We then systematically compared Trop-2 mRNA and protein levels in tumours with their tissues of origin. We find that Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Thus, we investigated the outcome of Trop-2 upregulation on tumour growth. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. On the other hand, we found no evidence of tumour-associated TROP2 mutations, nor of TROP2 induction of oncogenic transformation per se. Our data support a model where above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.

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baby rat kidney

CD1-T2 :



expressed sequence tags


heat-shock transcription factor 1




monoclonal antibody


polyclonal antibody


electron microscopy


multiple endocrine neoplasia type 2A

mutRAS :

mutated Harvey RAS




serial analysis of gene expression


small inhibitory RNA

wtRAS :

wild-type Harvey RAS.


  1. Fornaro M, Dell’Arciprete R, Stella M, Bucci C, Nutini M, Capri MG et al. Cloning of the gene encoding TROP-2, a cell-surface glycoprotein expressed by human carcinomas. Int J Cancer 1995; 62: 610–618.

    Article  CAS  Google Scholar 

  2. Ripani E, Sacchetti A, Corda D, Alberti S . The human Trop-2 is a tumor-associated calcium signal transducer. Int J Cancer 1998; 76: 671–676.

    Article  CAS  Google Scholar 

  3. Goldstein AS, Stoyanova T, Witte ON . Primitive origins of prostate cancer: in vivo evidence for prostate-regenerating cells and prostate cancer-initiating cells. Mol Oncol 2010; 4: 385–396.

    Article  Google Scholar 

  4. Wang J, Day R, Dong Y, Weintraub SJ, Michel L . Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers. Mol Cancer Ther 2008; 7: 280–285.

    Article  CAS  Google Scholar 

  5. Klein CE, Hartmann B, Schön MP, Weber L, Alberti S . Expression of 38-kD cell-surface glycoprotein in transformed human keratinocyte cell lines, basal cell carcinomas, and epithelial germs. J Invest Dermatol 1990; 95: 74–82.

    Article  CAS  Google Scholar 

  6. Cubas R, Zhang S, Li M, Chen C, Yao Q . Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer 2010; 9: 253.

    Article  Google Scholar 

  7. Basu A, Goldenberg DM, Stein R . The epithelial/carcinoma antigen EGP-1, recognized by monoclonal antibody RS7-3G11, is phosphorylated on serine 303. Int J Cancer 1995; 62: 472–479.

    Article  CAS  Google Scholar 

  8. Trerotola M, Rathore S, Goel HL, Li J, Alberti S, Piantelli M et al. Trop-2 and α2β1 integrin surface receptors as markers of putative human prostate cancer stem cells. Am J Transl Res 2010; 2: 135–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fong D, Moser P, Krammel C, Gostner JM, Margreiter R, Mitterer M et al. High expression of TROP2 correlates with poor prognosis in pancreatic cancer. Br J Cancer 2008; 99: 1290–1295.

    Article  CAS  Google Scholar 

  10. Muhlmann G, Spizzo G, Gostner J, Zitt M, Maier H, Moser P et al. TROP2 expression as prognostic marker for gastric carcinoma. J Clin Pathol 2009; 62: 152–158.

    Article  CAS  Google Scholar 

  11. Fong D, Spizzo G, Gostner JM, Gastl G, Moser P, Krammel C et al. TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity. Mod Pathol 2008; 21: 186–191.

    Article  CAS  Google Scholar 

  12. Ohmachi T, Tanaka F, Mimori K, Inoue H, Yanaga K, Mori M . Clinical significance of TROP2 expression in colorectal cancer. Clin Cancer Res 2006; 12: 3057–3063.

    Article  CAS  Google Scholar 

  13. Fang YJ, Lu ZH, Wang GQ, Pan ZZ, Zhou ZW, Yun JP et al. Elevated expressions of MMP7, TROP2, and survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer. Int J Colorectal Dis 2009; 24: 875–884.

    Article  CAS  Google Scholar 

  14. Bignotti E, Todeschini P, Calza S, Falchetti M, Ravanini M, Tassi RA et al. Trop-2 overexpression as an independent marker for poor overall survival in ovarian carcinoma patients. Eur J Cancer 2010; 46: 944–953.

    Article  CAS  Google Scholar 

  15. Cubas R, Li M, Chen C, Yao Q . Trop2: a possible therapeutic target for late stage epithelial carcinomas. Biochim Biophys Acta 2009; 1796: 309–314.

    CAS  PubMed  Google Scholar 

  16. Varughese J, Cocco E, Bellone S, de Leon M, Bellone M, Todeschini P et al. Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer 2011; 117: 3163–3172.

    Article  CAS  Google Scholar 

  17. Alberti S, Miotti S, Stella M, Klein CE, Fornaro M, Ménard S et al. Biochemical characterization of Trop-2, a cell surface molecule expressed by human carcinomas: formal proof that the monoclonal antibodies T16 and MOv-16 recognize Trop-2. Hybridoma 1992; 11: 539–535.

    Article  CAS  Google Scholar 

  18. Klein CEK, Cordon-Cardo C, Soehnchen R, Cote RJ, Oettgen HF, Eisinger M et al. Changes in cell surface glycoprotein expression during differentiation of human keratinocytes. J Invest Dermatol 1987; 89: 500–506.

    Article  CAS  Google Scholar 

  19. Fradet Y, Cordon-Cardo C, Thomson T, Daly ME, Whitmore Jr WF, Lloyd KO et al. Cell-surface antigens of human bladder cancer defined by mouse monoclonal antibodies. Proc Natl Acad Sci USA 1984; 81: 224–228.

    Article  CAS  Google Scholar 

  20. Cordon-Cardo C, Bander NH, Fradet Y, Finstad CL, Whitmore WF, Lloyd KO et al. Immunoanatomic dissection of the human urinary tract by monoclonal antibodies. J Histochem Cytochem 1984; 32: 1035–1040.

    Article  CAS  Google Scholar 

  21. Lipinski M, Parks DR, Rouse RV, Herzenberg LA . Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci USA 1981; 78: 5147–5150.

    Article  CAS  Google Scholar 

  22. Trerotola M, Guerra E, Alberti S . Letter to the editor: efficacy and safety of anti-Trop antibodies. Biochim Biophys Acta 2010; 1805: 119–120.

    CAS  PubMed  Google Scholar 

  23. Lal A, Lash AE, Altschul SF, Velculescu V, Zhang L, McLendon RE et al. A public database for gene expression in human cancers. Cancer Res 1999; 59: 5403–5407.

    CAS  Google Scholar 

  24. Carletti E, Guerra E, Alberti S . The forgotten variables of DNA array hybridization. Trends Biotechnol 2006; 24: 443–448.

    Article  CAS  Google Scholar 

  25. Nakashima K, Shimada H, Ochiai T, Kuboshima M, Kuroiwa N, Okazumi S et al. Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinoma. Int J Cancer 2004; 112: 1029–1035.

    Article  CAS  Google Scholar 

  26. Zhang L, Zhou W, Velculescu VE, Kern SE, Hruban RH, Hamilton SR et al. Gene expression profiles in normal and cancer cells. Science 1997; 276: 1268–1272.

    Article  CAS  Google Scholar 

  27. Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M et al. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 2009; 11: 162–171.

    Article  CAS  Google Scholar 

  28. Sukhthankar M, Alberti S, Baek SJ . Epigallocatechin-3-Gallate (EGCG) post-transcriptionally and post-translationally suppresses the cell proliferative protein TROP2 in human colorectal cancer cells. Anticancer Res 2010; 30: 2497–2503.

    CAS  PubMed  Google Scholar 

  29. Alberti S, Bucci C, Fornaro M, Robotti A, Stella M . Immunofluorescence analysis in flow cytometry: better selection of antibody-labeled cells after fluorescence overcompensation in the red channel. J Histochem Cytochem 1991; 39: 701–706.

    Article  CAS  Google Scholar 

  30. Alberti S, Parks DR, Herzenberg LA . A single laser method for subtraction of cell autofluorescence in flow cytometry. Cytometry 1987; 8: 114–119.

    Article  CAS  Google Scholar 

  31. Guerra E, Trerotola M, Dell’ Arciprete R, Bonasera V, Palombo B, El-Sewedy T et al. A bi-cistronic Cyclin D1-TROP2 mRNA chimera demonstrates a novel oncogenic mechanism in human cancer. Cancer Res 2008; 68: 8113–8121.

    Article  CAS  Google Scholar 

  32. Thorgeirsson UP, Turpeenniemi-Hujanen T, Williams JE, Westin EH, Heilman CA, Talmadge JE et al. NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. Mol Cell Biol 1985; 5: 259–262.

    Article  CAS  Google Scholar 

  33. Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  CAS  Google Scholar 

  34. El-Sewedy T, Fornaro M, Alberti S . Cloning of the mouse Trop2 gene - Conservation of a PIP2-binding sequence in the cytoplasmic domain of Trop-2. Int J Cancer 1998; 75: 324–331.

    Article  CAS  Google Scholar 

  35. Solimini NL, Luo J, Elledge SJ . Non-oncogene addiction and the stress phenotype of cancer cells. Cell 2007; 130: 986–988.

    Article  CAS  Google Scholar 

  36. Wang J, Zhang K, Grabowska D, Li A, Dong Y, Day R et al. Loss of trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma. Mol Cancer Res 2011; 9: 1686–1695.

    Article  CAS  Google Scholar 

  37. Zanna P, Trerotola M, Vacca G, Bonasera V, Palombo B, Guerra E et al. Trop-1 is a novel cell growth stimulatory molecule that marks early stages of tumor progression. Cancer 2007; 110: 452–464.

    Article  CAS  Google Scholar 

  38. Dai C, Whitesell L, Rogers AB, Lindquist S . Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 2007; 130: 1005–1018.

    Article  CAS  Google Scholar 

  39. Naquet P, Lepesant H, Luxembourg A, Brekelmans P, Devaux C, Pierres M . Establishment and characterization of mouse thymic epithelial cell lines. Thymus 1989; 13: 217–226.

    CAS  PubMed  Google Scholar 

  40. Alberti S, Herzenberg LA . DNA methylation prevents transfection of genes for specific surface antigens. Proc Natl Acad Sci USA 1988; 85: 8391–8394.

    Article  CAS  Google Scholar 

  41. Orsulic S, Li Y, Soslow RA, Vitale-Crosss LA, Gutkind JS, Varmus HE . Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell 2002; 1: 53–62.

    Article  CAS  Google Scholar 

  42. Erba E, Ubezio P, Pepe S, Vaghi M, Marsoni S, Torri W et al. Flow cytometric analysis of DNA content in human ovarian cancers. Br J Cancer 1989; 60: 45–50.

    Article  CAS  Google Scholar 

  43. Gossen M, Bujard H . Tight control of gene expression in mammalian cells by tetracycline- responsive promoters. Proc Natl Acad Sci USA 1992; 89: 5547–5551.

    Article  CAS  Google Scholar 

  44. No D, Yao TP, Evans RM . Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc Natl Acad Sci USA 1996; 93: 3346–3351.

    Article  CAS  Google Scholar 

  45. Wolter S, Mushinski JF, Saboori AM, Resch K, Kracht M . Inducible expression of a constitutively active mutant of mitogen-activated protein kinase kinase 7 specifically activates c-JUN NH2-terminal protein kinase, alters expression of at least nine genes, and inhibits cell proliferation. J Biol Chem 2002; 277: 3576–3584.

    Article  CAS  Google Scholar 

  46. Alberti S, Fornaro M . Higher transfection efficiency of genomic DNA purified with a guanidinium-thiocyanate-based procedure. Nucleic Acids Res 1990; 18: 351–353.

    Article  CAS  Google Scholar 

  47. Kistner A, Gossen M, Zimmermann F, Jerecic J, Ullmer C, Lubbert H et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 1996; 93: 10933–10938.

    Article  CAS  Google Scholar 

  48. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 494–498.

    Article  CAS  Google Scholar 

  49. Chalk AM, Wahlestedt C, Sonnhammer EL . Improved and automated prediction of effective siRNA. Biochem Biophys Res Commun 2004; 319: 264–274.

    Article  CAS  Google Scholar 

  50. Brummelkamp TR, Bernards R, Agami R . A system for stable expression of short interfering RNAs in mammalian cells. Science 2002; 296: 550–553.

    Article  CAS  Google Scholar 

  51. Alberti S, Nutini M, Herzenberg LA . DNA methylation prevents the amplification of TROP1, a tumor associated cell surface antigen gene. Proc Natl Acad Sci USA 1994; 91: 5833–5837.

    Article  CAS  Google Scholar 

  52. Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, Wiltshire T et al. Large-scale analysis of the human and mouse transcriptomes. PNAS 2002; 99: 4465–4470.

    Article  CAS  Google Scholar 

  53. Bonasera V, Alberti S, Sacchetti A . Protocol for high-sensitivity/long linear-range spectrofluorimetric DNA quantification using ethidium bromide. BioTechniques 2007; 43: 173–176.

    Article  CAS  Google Scholar 

  54. Querzoli P, Pedriali M, Rinaldi R, Lombardi AR, Biganzoli E, Boracchi P et al. Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients. Clin Cancer Res 2006; 12: 6696–6701.

    Article  CAS  Google Scholar 

  55. Polishchuk RS, Polishchuk EV, Marra P, Alberti S, Buccione R, Luini A et al. Correlative light-electron microscopy reveals the saccular-tabular ultrastructure of carriers operating between the Golgi apparatus and the plasma membrane. J Cell Biol 2000; 148: 45–58.

    Article  CAS  Google Scholar 

  56. Brown WJ, Farquhar MG . Immunoperoxidase methods for the localization of antigens in cultured cells and tissue sections by electron microscopy. Methods Cell Biol 1989; 31: 553–569.

    Article  CAS  Google Scholar 

  57. Tomayko MM, Reynolds CP . Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 1989; 24: 148–154.

    Article  CAS  Google Scholar 

  58. Rossi C, Di Lena A, La Sorda R, Lattanzio R, Antolini L, Patassini C et al. Intestinal tumour chemoprevention with the antioxidant lipoic acid stimulates the growth of breast cancer. Eur J Cancer 2008; 44: 2696–2704.

    Article  CAS  Google Scholar 

  59. Shi L, Campbell G, Jones WD, Campagne F, Wen Z, Walker SJ et al. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models. Nat Biotechnol 2010; 28: 827–838.

    Article  CAS  Google Scholar 

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We are grateful to Professor B Ponder and Dr S Martin for the generous supply of the genomic DNA of MEN-2A, pheochromocytoma and medullary thyroid carcinomas. We thank Dr A Mironov and GV Beznoussenko for help during the course of this work. This research was supported by the Fondazione of the Cassa di Risparmio della Provincia di Chieti, ABO Foundation (CH01D0081), Fondazione compagnia di San Paolo and Italian Ministry of Health (RicOncol RF-EMR-2006-361866). MT was a recipient of a scholarship from the Italian Foundation for Cancer Research (FIRC, Italy).

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Trerotola, M., Cantanelli, P., Guerra, E. et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene 32, 222–233 (2013).

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  • Trop-2
  • human tumours
  • cell growth
  • signalling
  • oncogene

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