Breast Cancer Research and Treatment

, Volume 143, Issue 2, pp 393–401 | Cite as

The role of genes co-amplified with nicastrin in breast invasive carcinoma

  • A. Sarajlić
  • A. Filipović
  • V. Janjić
  • R. C. Coombes
  • N. Pržulj
Brief Report

Abstract

Breast cancer accounts for more than 450,000 deaths per year worldwide. Discovery of novel therapeutic targets that will allow patient-tailored treatment of this disease is an emerging area of scientific interest. Recently, nicastrin has been identified as one such therapeutic target. Its overexpression is indicative of worse overall survival in the estrogen-receptor-negative patient population. In this paper, we analyze data from a large invasive breast carcinoma study and confirm nicastrin amplification. In search for genes that are co-amplified with nicastrin, we identify a potential novel breast cancer-related amplicon located on chromosome 1. Furthermore, we search for “influential interactors,” i.e., genes that interact with a statistically significantly high number of genes which are co-amplified with nicastrin, and confirm their involvement in this female neoplasm. Among the influential interactors, we find genes which belong to the core diseasome (a recently identified therapeutically relevant set of genes which is known to drive disease formation) and propose that they might be important for breast cancer onset, and serve as its novel therapeutic targets. Finally, we identify a pathway that may play a role in nicastrin’s amplification process and we experimentally confirm downstream signaling mechanism of nicastrin in breast cancer cells.

Keywords

Breast invasive carcinoma Nicastrin Co-amplified genes Protein–protein interaction network 

References

  1. 1.
    American Cancer Society (2011) Global cancer facts and figures 2nd edition. American Cancer Society, AtlantaGoogle Scholar
  2. 2.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352PubMedCentralPubMedGoogle Scholar
  3. 3.
    Lehmann B, Bauer J, Chen X, Sanders M, Chakravarthy A, Shyr Y, Pietenpol J (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig 121(7):2750–2767PubMedCrossRefGoogle Scholar
  4. 4.
    Sahlberg KK, Hongisto V, Edgren H, Makela R, Hellstrom K, Due EU, Vollan HKM, Sahlberg N, Wolf M, Brresen-Dale AL, Perl M, Kallioniemi O (2013) The {HER2} amplicon includes several genes required for the growth and survival of {HER2} positive breast cancer cells. Mol Oncol 7(3):392–401PubMedCrossRefGoogle Scholar
  5. 5.
    Orsetti B, Nugoli M, Cervera N, Lasorsa L, Chuchana P, Roug C, Ursule L, Nguyen C, Bibeau F, Rodriguez C, Theillet C (2006) Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q. Br J Cancer 95(10):1439–1447PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Filipović A, Gronau J, Green A, Wang J, Vallath S, Shao D, Rasul S, Ellis I, Yag E, Sturge J, Coombes R (2011) Biological and clinical implications of nicastrin expression in invasive breast cancer. Breast Cancer Res Treat 125(1):43–53PubMedCrossRefGoogle Scholar
  7. 7.
    Filipović A, Lombardo Y, Fronato M, Abrahams J, Aboagy E, Nguyen Q, Borda d’ Aqua B, Ridley A, Green A, Rahka E, Ellis I, Recchi C, Pržulj N, Sarajlić A, Alattia J, Fraering P, Mahendra D, Coombes R (2013) Monoclonal antibody targeting of nicastrin inhibits growth and metastasis of invasive breast cancer cells (Submitted)Google Scholar
  8. 8.
    Lombardo Y, Filipovic A, Molyneux G, Periyasamy M, Giamas G, Hu Y, Trivedi PS, Wang J, Yague E, Michel L, Coombes RC (2012) Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo. Proc Natl Acad Sci 109:16558–16563CrossRefGoogle Scholar
  9. 9.
    Cerami E, Gao J, Dogrusoz U (2012) The cbio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov (2):401–404Google Scholar
  10. 10.
    Sharan R, Ulitsky I, Shamir R (2007) Network-based prediction of protein function. Mol Syst Biol 3:88Google Scholar
  11. 11.
    Schwikowski B, Uetz P (2000) A network of protein–protein interactions in yeast. Nature Biotechnol 18:1257–1261PubMedCrossRefGoogle Scholar
  12. 12.
    Chua HN, Sung WK, Wong L (2006) Exploiting indirect neighbours and topological weight to predict protein function from protein–protein interactions. Bioinformatics 22(13):1623–1630PubMedCrossRefGoogle Scholar
  13. 13.
    Samanta MP, Liang S (2003) Predicting protein functions from redundancies in large-scale protein interaction networks. Proc Natl Acad Sci USA 100:12579–12583CrossRefGoogle Scholar
  14. 14.
    Ideker T, Sharan R (2008) Protein networks in disease. Genome Res 18:644–652PubMedCrossRefGoogle Scholar
  15. 15.
    Aragues R, Sander C, Oliva B (2008) Predicting cancer involvement of genes from heterogeneous data. BMC Bioinformatics 9(172):172PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Goldenberg A, Mostafavi S, Quon G, Boutros PC, Morris QD (2011) Unsupervised detection of genes of influence in lung cancer using biological networks. Bioinformatics 27(22):3166–3172PubMedCrossRefGoogle Scholar
  17. 17.
    Janjić V, Pržulj N (2012) The core diseasome. Mol Biosyst 8(10):2614–2625PubMedCrossRefGoogle Scholar
  18. 18.
    Ashworth A, Lord CJ, Reis-Filho JS (2011) Genetic interactions in cancer progression and treatment. Cell 145(1):30–38PubMedCrossRefGoogle Scholar
  19. 19.
    Chatr-aryamontri A, Breitkreutz BJ, Heinicke S, Boucher L, Winter A, Stark C, Nixon J, Ramage L, Kolas N, O’Donnell L, Reguly T, Breitkreutz A, Sellam A, Chen D, Chang C, Rust J, Livstone M, Oughtred R, Dolinski K, Tyers M (2013) The biogrid interaction database. Nucleic Acids Res 41(D1):D816–D823PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Collaboration (2012) Comprehensive molecular portraits of human breast tumours. Nat Biotechnol 490(7418):61–70Google Scholar
  21. 21.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B 57(1):289–300Google Scholar
  22. 22.
    Basik M, Caplen NJ, Kallioniemi OP, Mousses S (2003) Amplified genes as therapeutic targets in cancer. Targets 2(4):147–153CrossRefGoogle Scholar
  23. 23.
    Bakheet TM, Doig AJ (2008) Properties and identification of human protein drug targets. Bioinformatics 25(4):451–457CrossRefGoogle Scholar
  24. 24.
    Thompson L, Jiang J, Madamanchi N, Runge M, Patterson C (2001) Ptp-epsilon, a tyrosine phosphatase expressed in endothelium, negatively regulates endothelial cell proliferation. Am J Physiol Heart Circ Physiol 281(1):H396–403PubMedGoogle Scholar
  25. 25.
    Carr B, Wang Z, Kar S (2002) K vitamins, ptp antagonism, and cell growth arrest. J Cell Physiol 193(3)Google Scholar
  26. 26.
    Kikawa K, Vidale D, Van Etten R, Kinch M (2002) Regulation of the epha2 kinase by the low molecular weight tyrosine phosphatase induces transformation. J Biol Chem 277(42):39,274–9CrossRefGoogle Scholar
  27. 27.
    Ha TY (2009) The role of regulatory T cells in cancer. Immune Netw 9:209–235PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Balkwill F, Montfort A, Capasso M (2013) B regulatory cells in cancer. Trends Immunol 34(4):169–173PubMedCrossRefGoogle Scholar
  29. 29.
    Zamai L, Ponti C, Mirandola P, Gobbi G, Papa S, Galeotti L, Cocco L, Vitale M (2007) Nk cells and cancer. J Immunol 178(7):4011–4016PubMedGoogle Scholar
  30. 30.
    Ray M, Ruan J, Zhang W (2008) Variations in the transcriptome of Alzheimer’s disease reveal molecular networks involved in cardiovascular diseases. Genome Biol 9(10):R148PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Aihara T, Miyoshi Y, Koyama K, Suzuki M, Takahashi E, Monden M, Nakamura Y (1998) Cloning and mapping of smarca5 encoding hsnf2h, a novel human homologue of drosophila iswi. Cytogenet Genome Res 81(3–4):191–193CrossRefGoogle Scholar
  32. 32.
    Champoux JJ (2001) Dna topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70(1):369–413PubMedCrossRefGoogle Scholar
  33. 33.
    Cenciarelli C, Chiaur D, Guardavaccaro D, Parks W, Vidal M, Pagano M (1999) Identification of a family of human F-box proteins. Curr Biol 9(20):1177–S3PubMedCrossRefGoogle Scholar
  34. 34.
    Patton E, Willems AR, Tyers M (1998) Combinatorial control in ubiquitin-dependent proteolysis: don’t skp the F-box hypothesis. Trends Genet 14(6):236–243PubMedCrossRefGoogle Scholar
  35. 35.
    Clarke MF, Liu R (2006) Compositions and methods for treating and diagnosing cancer. Google Patents, US Patent App. 10/864,207Google Scholar
  36. 36.
    Ouimet M, Cassart P, Larivire M, Kritikou E, Simard J, Sinnett D (2012) Functional analysis of promoter variants in ku70 and their role in cancer susceptibility. Genes Chromosomes Cancer 51(11):1007–1011PubMedCrossRefGoogle Scholar
  37. 37.
    Chu IM, Hengst L, Slingerland JM (2008) The cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8(4):253–267PubMedCrossRefGoogle Scholar
  38. 38.
    Abdelmohsen K, Gorospe M (2010) Posttranscriptional regulation of cancer traits by hur. Wiley Interdiscip Rev RNA 1(2):214–229PubMedCrossRefGoogle Scholar
  39. 39.
    Kazarian M, Laird-Offringa IA (2011) Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy. Mol Cancer 10(1):33PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Tangye SG, Phillips JH, Lanier LL (2000) The cd2-subset of the ig superfamily of cell surface molecules: receptor–ligand pairs expressed by nk cells and other immune cells. Semin Immunol 12(2):149–57PubMedCrossRefGoogle Scholar
  41. 41.
    Wagner K, Hemminki K, Grzybowska E, Klaes R, Butkiewicz D, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E, Försti A (2004) The insulin-like growth factor-1 pathway mediator genes: Shc1 met300val shows a protective effect in breast cancer. Carcinogenesis 25(12):2473–2478PubMedCrossRefGoogle Scholar
  42. 42.
    Wang X (2012) Abstract 2150: The role of shp2 in her2+ breast cancer. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research 72(8):1538–7445Google Scholar
  43. 43.
    Srinivasan D, Sims JT, Plattner R (2008) Aggressive breast cancer cells are dependent on activated abl kinases for proliferation, anchorage-independent growth and survival. Oncogene 27(8):1095–1105PubMedCrossRefGoogle Scholar
  44. 44.
    Mieyal J, Gallogly M, Qanungo S, Sabens E, Shelton M (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10(11):1941–1988PubMedCrossRefGoogle Scholar
  45. 45.
    McCann AH, Kirley A, Carney DN, Corbally N, Magee HM, Keating G, Dervan PA (1995) Amplification of the mdm2 gene in human breast cancer and its association with mdm2 and p53 protein status. Br J Cancer 71(5):981–985PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Hibbs ML, Harder KW (2006) The duplicitous nature of the Lyn tyrosine kinase in growth factor signaling. Growth Factors 24(2):137–149PubMedCrossRefGoogle Scholar
  47. 47.
    Choi YL, Bocanegra M, Kwon MJ, Shin YK, Nam SJ, Yang JH, Kao J, Godwin AK, Pollack JR (2010) Lyn is a mediator of epithelial–mesenchymal transition and a target of dasatinib in breast cancer. Cancer Res 70(6):2296–2306PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Donato R, Cannon B, Sorci G, Riuzzi F, Hsu K, Weber D, CL G (2013) Functions of s100 proteins. Antioxid Redox Signal 13(1):24–57Google Scholar
  49. 49.
    Hayashi I, Takatori S, Urano Y, Miyake Y, Takagi J, Sakata-Yanagimoto M, Iwanari H, Osawa S, Morohashi Y, Li T, Wong PC, Chiba S, Kodama T, Hamakubo T, Tomita T, Iwatsubo T (2012) Neutralization of the gamma-secretase activity by monoclonal antibody against extracellular domain of nicastrin. Oncogene 31:787–798PubMedCrossRefGoogle Scholar
  50. 50.
    Salama I, Malone P, Mihaimeed F, Jones J (2008) A review of the {S100} proteins in cancer. Eur J Surg Oncol (EJSO) 34(4):357–364CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • A. Sarajlić
    • 1
  • A. Filipović
    • 2
  • V. Janjić
    • 1
  • R. C. Coombes
    • 2
  • N. Pržulj
    • 1
  1. 1.Department of ComputingImperial College LondonLondonUK
  2. 2.Department of Surgery and CancerFaculty of Medicine, Imperial College London LondonUK

Personalised recommendations