Skip to main content
Log in

Functional Proteomics of Breast Cancer for Signal Pathway Profiling and Target Discovery

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The near completion of human genome sequencing and the introduction of mass spectrometry combined with advanced bioinformatics for protein identification have led to the emergence of proteomics as a powerful tool for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified proteins of potential clinical interest, such as the molecular chaperone 14-3-3 sigma and the heat shock protein HSP90, and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer cells. As illustrated by fibroblast growth factor-2 and the H19 noncoding oncogenic mRNA, proteomics is a pertinent approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth and metastasis. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast carcinogenesis and to identify new therapeutic targets. The next challenge will be the introduction of proteomics as a tool for the clinic, for the establishment of diagnosis, prognosis, and the monitoring of treatment; however, this ambitious goal still requires further technological progress in the field.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. K. L. Cheung, C. R. Graves, and J. F. Robertson (2000). Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat. Rev. 26:91–102.

    Google Scholar 

  2. D. R. Ciocca and R. Elledge (2000). Molecular markers for predicting response to tamoxifen in breast cancer patients. Endocrine 13:1–10.

    Google Scholar 

  3. D. Haber (2000). Roads leading to breast cancer. N. Engl. J. Med. 343:1566–1568.

    Google Scholar 

  4. C. K. Osborne (1998). Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339:1609–1618.

    Google Scholar 

  5. S. P. Ethier (1995). Growth factor synthesis and human breast cancer progression. J. Natl. Cancer Inst. 87:964–973.

    Google Scholar 

  6. X. F. LeBourhis, R. A. Toillon, B. Boilly, and H. Hondermarck (2000). Autocrine and paracrine growth inhibitors of breast cancer cells. Breast Cancer Res. Treat. 60:251–258.

    Google Scholar 

  7. N. Rahimi, W. Hung, E. Tremblay, R. Saulnier, and B. Elliott (1998). c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J. Biol. Chem. 273:33714–33721.

    Google Scholar 

  8. D. M. Ornitz and N. Itoh (2001). Fibroblast growth factors. Genome Biol. 2:3005.1–3005.12.

    Google Scholar 

  9. V. D. Blanckaert, M. Hebbar, M. M. Louchez, M. O. Vilain, M. E. Schelling, and J. P. Peyrat (1998). Basic Fibroblast growth factor and their prognostic value in human breast cancer. Clin. Cancer Res. 4:2939–2947.

    Google Scholar 

  10. V. Nurcombe, C. E. Smart, H. Chipperfield, S. M. Cool, B. Boilly, and H. Hondermarck (2000). The proliferative and migratory activities of breast cancer cells can be differentially regulated by heparan sulfates. J. Biol. Chem. 275:30009–30018.

    Google Scholar 

  11. H. Rahmoune, H. L. Chen, J. T. Gallagher, P. S. Rudland, and D. G. Fernig (1998). Interaction of heparan sulfate from mammary gland cells with acid fibroblast growth factor and basic FGF. Regulation of the activity ofbFGFby high and low affinity binding sites in heparan sulfate. J. Biol. Chem. 273:7303–7310.

    Google Scholar 

  12. B. Boilly, A. S. Vercoutter-Edouart, H. Hondermarck, V. Nurcombe, and X. Le Bourhis (2000). Fibroblast growth factor signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev. 11:295–302.

    Google Scholar 

  13. S. Descamps, X. Lebourhis, M. Delehedde, B. Boilly, and H. Hondermarck (1998). Nerve growth factor is mitogenic for cancerous but not normal human breast epithelial cells. J. Biol. Chem. 273:16659–16662.

    Google Scholar 

  14. S. Descamps, R. A. Toillon, E. Adriaenssens, V. Pawlowski, S. M. Cool, V. Nurcombe, X. Le Bourhis, B. Boilly, J. P. Peyrat, and H. Hondermarck (2001). Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J. Biol. Chem. 276:17864–17870.

    Google Scholar 

  15. E. Tagliabue, F. Castiglioni, C. Ghirelli, M. Modugno, L. Asnaghi, C. Melani, and S. Menard (2000). Nerve growth factor cooperates with p185HER-2 in activating growth of human breast carcinoma cells. J. Biol. Chem. 275:5388–5394.

    Google Scholar 

  16. A. Chiarenza, P. Lazarovici, L. Lempereur, G. Cantarelle, A. Bianchi, and R. Bernardini (2001). Tamoxifen inhibits nerve growth factor-induced proliferation of the human breast cancerous cell line. Cancer Res. 61:3002–3008.

    Google Scholar 

  17. J. Bonneterre, J. P. Peyrat, R. Beuscart, and A. Demaille (1990). Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Res. 50:6931–6935.

    Google Scholar 

  18. V. D. Blanckaert, M. Hebbar, M. M. Louchez, M. O. Vilain, M. E. Schelling, and J. P. Peyrat (1998). Basic fibroblast growth factor receptors and their prognostic value in human breast cancer. Clin. Cancer Res. 4:2939–2947.

    Google Scholar 

  19. V. Pawlowski, F. Revillion, M. Hebbar, L. Hornez, and J. P. Peyrat (2000). Prognostic value of the type I growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin. Cancer Res. 6:4217–4225.

    Google Scholar 

  20. S. Descamps, V. Pawlowski, F. Revillion, L. Hornez, M. Hebbar, B. Boilly, H. Hondermarck, and J. P. Peyrat (2001). Expression of nerve growth factor receptors and their pronostic value in human breast cancer. Cancer Res. 61:4337–4340.

    Google Scholar 

  21. S. J. Nass, H. A. Hahm, and N. E. Davidson (1998). Breast cancer biology blossoms in the clinic. Nat. Med. 4:761–762.

    Google Scholar 

  22. H. Hondermarck, C. S. McLaughlin, S. D. Patterson, and R. A. Bradshaw (1994). Early changes in protein synthesis induced by basic fibroblast growth factor, nerve growth factor, and epidermal growth factor in PC12 pheochromocytoma cells. Proc. Natl. Acad. Sci. U.S.A. 91:9377–9381.

    Google Scholar 

  23. V. Soskic, M. Gorlach, S. Poznanovic, F. D. Boehmer, and J. Godovac-Zimmermann (1999). Functional proteomics analysis of signal transduction pathways of the plateletderived growth factor beta receptor. Biochemistry 38:1757–1764.

    Google Scholar 

  24. A. Pandey, A. V. Podtelejnikov, B. Blagoev, X. R. Bustelo, M. Mann, and H. F. Lodish (2000). Analysis of receptor signaling pathways by mass spectrometry: Identification of vav-2 as a substrate of the epidermal and platelet-derived growth factor receptors. Proc. Natl. Acad. Sci. U.S.A. 97:179–184.

    Google Scholar 

  25. J. F. Liu, E. Chevet, S. Kebache, G. Lemaitre, D. Barritault, L. Larose, and M. Crepin (1999). Functional Rac-1 and Nck signaling networks are required for FGF-2-induced DNA synthesis in MCF-7 cells. Oncogene 18:6425–6433.

    Google Scholar 

  26. A. S. Vercoutter-Edouart, J. Lemoine, C. E. Smart, V. Nurcombe, B. Boilly, J. P. Peyrat, and H. Hondermarck (2000). The mitogenic signaling pathway for fibroblast growth factor-2 involves the tyrosine phosphorylation of cyclin D2 in MCF-7 human breast cancer cells. FEBS Lett. 478:209–215.

    Google Scholar 

  27. A. S. Vercoutter-Edouart, X. Czeszak, M. Crepin, J. Lemoine, B. Boilly, X. Le Bourhis, J. P. Peyrat, and H. Hondermarck (2001). Proteomic detection of changes in protein synthesis induced by fibroblast growth factor-2 in MCF-7 human breast cancer cells. Exp. Cell Res. 262:59–68.

    Google Scholar 

  28. C. Jolly and R. I. Morimoto (2000). Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J. Natl. Cancer Inst. 92:1564–1572.

    Google Scholar 

  29. R. Colomer, L. A. Shamon, M. S. Tsai, and R. Lupu (2001). Herceptin: From the bench to the clinic. Cancer Invest. 19:49–56.

    Google Scholar 

  30. L. H. Pearl and C. Prodromou (2000). Structure and in vivo function of HSP90. Curr. Opin. Struct. Biol. 10:46–51.

    Google Scholar 

  31. H. Fu, R. R. Subramanian, and S. C. Masters (2000). 14-3-3 proteins: Structure, function, and regulation. Annu. Rev. Pharmacol. Toxicol. 40:617–647.

    Google Scholar 

  32. A. S. Vercoutter-Edouart, J. Lemoine, X. Le Bourhis, H. Louis, B. Boilly, V. Nurcombe, F. Revillion, J. P. Peyrat, and H. Hondermarck (2001). Proteomic analysis reveals that 14-3-3 sigma is down-regulated in human breast cancer cells. Cancer Res. 61:76–80.

    Google Scholar 

  33. A. T. Ferguson, E. Evron, C. B. Umbricht, T. K. Pandita, T. A. Chan, H. Hermeking, J. R. Marks, A. R. Lambers, P. A. Futreal, M. R. Stampfer, and S. Sukumar (2000). High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc. Natl. Acad. Sci. U.S.A. 97:6049–6054.

    Google Scholar 

  34. S. Li and G. D. Shipley (1991). Expression of multiple species of basic fibroblast growth factor mRNA and protein in normal and tumor-derived mammary epithelial cells in culture. Cell Growth Differ. 2:195–202.

    Google Scholar 

  35. H. Hermeking, C. Lengauer, K. Polyak, T. C. He, L. Zhang, S. Thiagalingam, K. W. Kinzler, and B. Vogelstein (1997). 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol. Cell 1:3–11.

    Google Scholar 

  36. C. Laronga, H. Y. Yang, C. Neal, and M. H. Lee (2000). Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. J. Biol.Chem. 275:23106–23112.

    Google Scholar 

  37. C. I. Brannan, E. C. Dees, R. S. Ingram, and S. M. Tilghman (1990). The product of the H19 gene may function as an RNA. Mol. Cell. Biol. 10:28–36.

    Google Scholar 

  38. Y. Hao, T. Crenshaw, T. Moulton, E. Newcomb, and B. Tycko (1993). Tumour-suppressor activity of H19 RNA. Nature 365:764–767.

    Google Scholar 

  39. E. Adriaenssens, S. Lottin, N. Berteaux, L. Hornez, W. Fauquette, V. Fafeur, J. P. Peyrat, X. Le Bourhis, H. Hondermarck, J. Coll, T. Dugimont, and J. J. Curgy (2002). Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells. Exp. Cell Res. 275:215–229.

    Google Scholar 

  40. S. Lottin, E. Adriaenssens, T. Dupressoir, N. Berteaux, C. Montpellier, J. Coll, T. Dugimont, and J. J. Curgy (2002). Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis, 23:1885–1895.

    Google Scholar 

  41. S. Lottin, A. S. Vercoutter-Edouart, E. Adriaenssens, X. Czeszak, J. Lemoine, M. Roudbaraki, J. Coll, H. Hondermarck, T. Dugimont, and J. J. Curgy (2002). Thioredoxin post-transcriptional regulation by H19 provides a new function to mRNA-like non-coding RNA. Oncogene 21:1625–1631.

    Google Scholar 

  42. H. Nakamura, K. Nakamura, and J. Yodoi (1997). Redox regulation of cellular activation. Annu. Rev. Immunol. 15:351–369.

    Google Scholar 

  43. K. Hirota, M. Murata, T. Itoh, J. Yodoi, and K. Fukuda (2001). Redox-sensitive transactivation of epidermal growth factor receptor by tumor necrosis factor confers the NF-kappa B activation. J. Biol. Chem. 276:25953–25958.

    Google Scholar 

  44. G. L. Wright, Jr. (1974). Two-dimensional acrylamide gel electrophoresis of cancer-patient serum proteins. Annu. Clin. Lab. Sci. 4:281–293.

    Google Scholar 

  45. B. Westley and H. Rochefort (1980). A secreted glycoprotein induced by estrogen in human breast cancer cell lines. Cell 20:353–362.

    Google Scholar 

  46. D. K. Trask, V. Band, D. A. Zajchowski, P. Yaswen, T. Suh, and R. Sager (1990). Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 87:2319–2323.

    Google Scholar 

  47. J. Stastny, R. Prasad, and E. Fosslien (1984). Tissue proteins in breast cancer, as studied by use of two-dimensional electrophoresis. Breast Cancer Res. Treat. 30:1914–1918.

    Google Scholar 

  48. P. J. Wirth, V. Egilsson, V. Gudnason, S. Ingvarsson, and S. S. Thorgeirsson (1987). Specific polypeptide differences in normal versus malignant human breast tissues by two-dimensional electrophoresis. Breast Cancer Res. Treat. 10:177–189.

    Google Scholar 

  49. P. J. Wirth (1989). Specific polypeptide differences in normal versus malignant breast tissue by two-dimensional electrophoresis. Electrophoresis 10:543–554.

    Google Scholar 

  50. P. J. Worland, D. Bronzert, R. B. Dickson, M. E. Lippman, L. Hampton, S. S. Thorgeirsson, and P. J. Wirth (1989). Secreted and cellular polypeptide patterns of MCF-7 human breast cancer cells following either estrogen stimulation or v-H-ras transfection. Cancer Res. 49:51–57.

    Google Scholar 

  51. T. M. Maloney, P. L. Paine, and J. Russo (1989). Polypeptide composition of normal and neoplastic human breast tissues and cells analyzed by two-dimensional gel electrophoresis. Breast Cancer Res. Treat. 14:337–348.

    Google Scholar 

  52. R. A. Craven and R. E. Banks (2001). Laser capture microdissection and proteomics: Possibilities and limitation. Proteomics 1:1200–1204.

    Google Scholar 

  53. S. P. Gygi, B. Rist, S. A. Gerber, F. Turecek, M. H. Gelb, and R. Aebersold (1999). Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat. Biotechnol. 17:994–999.

    Google Scholar 

  54. H. J. Issaq (2001). The role of separation science in proteomics research. Electrophoresis 22:3629–3638.

    Google Scholar 

  55. S. R. Weinberger, T. S. Morris, and M. Pawlak (2000). Recent trends in protein biochip technology. Pharmacogenomics 1:395–416.

    Google Scholar 

  56. K. K. Jain (2002). Post-genomic applications of lab-on-a-chip and microarrays. Trends Biotechnol. 20:184–185.

    Google Scholar 

  57. R. W. Nelson, D. Nedelkov, and K. A. Tubbs (2000). Biosensor chip mass spectrometry: A chip-based proteomics approach. Electrophoresis 21:1155–1163.

    Google Scholar 

  58. E. T. Fung, V. Thulasiraman, S. R. Weinberger, and E. A. Dalmasso (2001). Protein biochips for differential profiling. Curr. Opin. Biotechnol. 12:65–69.

    Google Scholar 

  59. J. E. Celis, M. Kruhoffer, I. Gromova, C. Frederiksen, M. Ostergaard, T. Thykjaer, P. Gromov, J. Yu, H. Palsdottir, N. Magnusson, and T. F. Orntoft (2000). Gene expression profiling: Monitoring transcription and translation products using DNA microarrays and proteomics. FEBS Lett. 480:2–16.

    Google Scholar 

  60. S. M. Hanash (2001). Global profiling of gene expression in cancer using genomics and proteomics. Curr. Opin. Mol. Ther. 3:538–545.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hubert Hondermarck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hondermarck, H., Dollé, L., Yazidi-Belkoura, I.E. et al. Functional Proteomics of Breast Cancer for Signal Pathway Profiling and Target Discovery. J Mammary Gland Biol Neoplasia 7, 395–405 (2002). https://doi.org/10.1023/A:1024086015542

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1024086015542

Navigation