Abstract
An understanding of the complexity of cancer is important for correct diagnostics and efficient treatment of this disease. Recent developments of proteomics technologies allow us to address the complexity of tumorigenesis at a level of global protein profiling. This review discusses recent studies of signaling processes in cells of epithelial origin undertaken with the use of global protein profiling. Tumors of epithelial origin comprise about 90% of human breast cancers, and it is believed that transformation of breast epithelial cells shares common features of transformation with other mammalian cells: destabilization of the genome followed by acquisition of immortalization, unrestricted growth, evasion of death-inducing signals, and acquisition of invasive and tumor promoting characteristics. Functional proteomics of growth-promoting, growth-inhibiting, and pro-apoptotic signaling pathways, in combination with proteomics studies of breast epithelial cell differentiation and profiling of breast tumorigenesis, revealed groups of regulated proteins: structural components, stress-regulated proteins, regulators of transcription, translation and RNA processing, and regulators of posttranslational modifications, e.g., kinases, phosphatases, and proteases. The first lesson of proteomics studies is the discovery of significant number of new targets, as compared to total number of affected proteins. The second lesson is the poor correlation between expressions of proteins and their mRNAs. The third lesson is the low amplitude of protein changes compared to that observed for mRNA. These observations also recommend the analysis of signaling patterns rather than separate signaling pathways.
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REFERENCES
R. S. Cotran, S. L. Robbins, and V. Kumar (1994). The breast. In Robbins' Pathologic Basis of Disease, 5th edn., Saunders, Philadelphia, pp. 1089–1111.
J. Taylor-Papadimitriou and E. B. Lane (1987). The Mammary gland: Development, Regulation and Function, Plenum, New York, pp. 181–215.
D. Hanahan and R. Weinberg (2000). The hallmarks of cancer. Cell 100:57–70.
A. R. Venkitaraman (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182.
I. Bíeche and R. Lidereau (1995). Genetic alterations in breast cancer. Genes Chromosom. Cancer 14:227–251.
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 pro-filing: Monitoring transcription and translation products using DNA microarrays and proteomics. FEBS Lett. 480:2–16.
S. M. Hanash, M. P. Bobek, D. S. Rickman, T. Williams, J. M. Rouillard, R. Kuick, and E. Puravs. (2002). Integrating cancer genomics and proteomics in the post-genome era. Proteomics 2:69–75.
R. F. Servant (2001). High-speed biologists search for gold in proteins. Science 294:2074–2083.
R. Westermeier and T. Naven (2002). Proteomics in Practice, Wiley-VCH, Weinheim.
T. Rabilloud (ed.) (2000). Proteome Research: Two-Dimensional Gel Electrophoresis and Identification Methods, Springer, Heidelberg, Germany.
C. Dickson, B. Spencer-Dene, C. Dillon, and V. Fantl (2000). Tyrosine kinase signalling in breast cancer: Fibroblast growth factors and their receptors. Breast Cancer Res. 2:191–196.
E. Fenig, R. Wieder, S. Paglin, H. Wang, R. Persaud, A. Haimovitz-Friedman, Z. Fuks, and J. Yahalom (1997). Basic fibroblast growth factor confers growth inhibition and mitogenactivated protein kinase activation in human breast cancer cells. Clin. Cancer Res. 3:135–142.
A.-S. Vercoutter-Edouart, X. Czeszak, M. Crepin, J. Lemoin, B. Boilly, X. L. 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.
Z. Kelman (1997). PCNA: Structure, functions and interactions. Oncogene 14:629–641.
P. Thaw,N. J. Baxter, A. M. Hounslow, C. Price, J. P. Waltho, and C. J. Craven (2001). Structure ofTCTPreveals unexpected relationship with guanine nucleotide-free chaperones. Nat. Struct. Biol. 8:701–704.
L. Neckers (2002). HSP90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol. Med. 8:S55–S61.
M. Seddighzadeh, S. Linder, M. C. Shoshan, G. Auer, and A. A. Alaiya (2000). Inhibition of extracellular signal-regulated kinase 1/2 activity of the breast cancer cell line MDA-MB-231 leads to major alterations in the pattern of protein expression. Electrophoresis 21:2737–2743.
R. K. Rasmussen, H. Ji, J. S. Eddes, R. L. Moritz, G. E. Reid, R. J. Simpson, and D. S. Dorow (1998). Two-dimensional electrophoretic analysis of mixed lineage kinase 2 N-terminal domain binding proteins. Electrophoresis 19:809-817.
T. S. Lewis, J. B. Hunt, L. D. Aveline, K. R. Jonscher, D. F. Louie, J. M. Yeh, T. S. Nahreini, K. A. Resing, and N. G. Ahn (2000). Identification of novel MAP kinase pathway signaling targets by functional proteomics and mass spectrometry. Mol. Cell 6:1343–1354.
V. Soskic, M. Görlach, S. Poznanovic, F. D. Boehmer, and J. Godovac-Zimmermann (1999). Functional proteomics analysis of signal transduction pathways of the platelet-derived growth factor β receptor. Biochemistry 38:1757–1764.
C. H. Heldin, A. Ostman, and L. Ronnstrand (1998). Signal transduction via platelet-derived growth factor receptors. Biochim. Biophys. Acta 1378:F79–F113.
T.-Y. Ho, J. Russo, and I. H. Russo (1994). Polypeptide pattern of human breast epithelial cells following human chorionic gonadotropin treatment. Electrophoresis 15:746–750.
T. Kanamoto, U. Hellman, C.-H. Heldin, and S. Souchelnytskyi (2002). Functional proteomics of transforming growth factor-β1-stimulated Mv1Lu epithelial cells: Rad51 as a target of TGFβ1-dependent regulation of DNA repair. EMBO J. 21:1219–1230.
S. Prasad, V. A. Soldatenkov, G. Srinivasarao, and A. Dritschilo (1998). Identification of keratins 18, 19 and heat-shock protein 90 beta as candidate substrates of proteolysis during ionizing radiation-induced apoptosis of estrogen-receptor negative breast tumor cells. Int. J. Oncol. 13:757–764.
V. Badock, U. Steinhusen, K. Bommert, B. Wittmann-Liebold, and A. Otto (2001). Apoptosis-induced cleavage of keratin 15 and keratin 17 in a human breast epithelial cell line. Cell Death Differ. 8:308–315.
R. A. Toillon, S. Descamps, E. Adrienssens, J. M Ricort, D. Bernard, B. Boilly, and X. Le Bourhis (2002). Normal breast epithelial cells induce apoptosis of breast cancer cells via Fas signaling. Exp. Cell Res. 275:31–43.
C. Gerner, U. Fröhwein, J. Gotzmann, E. Bayer, D. Gelbmann, W. Bursch, and R. Schulte-Hermann (2000). The Fas-induced apoptosis analyzed by high throughput proteome analysis. J. Biol. Chem. 275:39018–39026.
B. Thiede, C. Dimmler, F. Siejak, and T. Rudel (2001). Predominant identification of RNA-binding proteins in Fas-induced apoptosis by proteome analysis. J. Biol. Chem. 276:26044–26050.
S.-T. Chen, T.-L. Pan, Y.-C. Tsai, and C.-M. Huang (2002). Proteomics reveals protein profile changes in doxorubicin-treated MCF-7 human breast cancer cells. Cancer Lett. 181:95–107.
S. Oesterreich, C. N. Weng, M. Qiu, S. G. Hilsenbeck, C. K. Osborne, and S. A. Fuqua (1993). The small heat shock protein hsp27 is correlated with growth and drug resistance in human breast cancer cell lines. Cancer Res. 53:4443–4448.
B. A. Gusterson, M. J. Warburton, D. Mitchell,M.Ellison, A. M. Neville, and P. S. Rudland (1982). Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Res. 42:4763–4770.
C. Péchoux, T. Gudjonsson, L. Ronnov-Jenssen, M. J. Bissell, and O. W. Petersen (1999). Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. Dev. Biol. 206:88–99.
M. J. Page, B. Amess, R. R. Townsed, R. Parekh, A. Herath, L. Brusten, M. J. Zvelebil, R. C. Stein, M. D. Waterfield, S. C. Davies, and M. J. O'Hare (1999). Proteomic definition of normal human luminal and myoepithelial breast cells purified from reduction mammoplasties. Proc. Natl. Acad. Sci. U.S.A. 96:12589–12594.
D. K. Trask, V. Band, D. A. Zajchkovski, 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.
B. Franzen, S. Linder, A. A. Alaiya, E. Eriksson, K. Fujioka, A.-C. Bergman, H. Jörnvall, and G. Auer. (1997). Analysis of polypeptide expression in benign and malignant human breast lesions. Electrophoresis 18:582–587.
A.-C. Bergman, T. Benjamin, A. Alaiya, M. Waltham, K. Sakaguchi, B. Franzen, S. Linder, T. Bergman, G. Auer, E. Appella, P. J. Wirth, and H. Jörnvall (2000). Identification of gel-separated tumor marker proteins by mass spectrometry. Electrophoresis 21:679–686.
L. Bini, B. Magi, B. Marzocchi, F. Arcuri, S. Tripodi, M. Cintorino, J.-C. Sanchez, S. Frutiger, G. Hughes, V. Pallini, D. Hochstrasser, and P. Tosi (1997). Protein expression profiles in human breast ductal carcinoma and histologically normal tissue. Electrophoresis 18:2832–2841.
J. D. Wulfkuhle, D. C. Sgroi, H. Krutzsch, K. McLean, K. McGarvey, M. Knowlton, S. Chen, H. Shu, A. Sahin, R. Kurek, D. Wallwiener, M. J. Merino, E. F. Petricoin III, Y. Zhao, and P. S. Steeg (2002). Proteomics of human breast ductal carcinoma in situ. Cancer Res. 62:6740–6749.
C. V. Dang and G. L. Semenza (1999) Oncogenic alterations of metabolism. Trends Biol. Sci. 24:68–72.
I. Pucci-Minafra, S. Fontana, P. Cancemi, G. Alaimo, and S. Minafra (2002). Proteomic patterns of cultured breast cancer cells and epithelial mammary cells. Ann. N.Y. Acad. Sci. 963:122–139.
K. Williams, C. Chubb, E. Huberman, and C. S. Giometti. (1998). Analysis of differential protein expression in normal and neoplastic human breast epithelial cell lines. Electrophoresis 19:333–343.
A.-S. Vercoutter-Edouart, J. Lemoine, X. L. Bourhis, H. Louis, B. Boilly, V. Nurcombe, F. Revillion, J.-P. Peyrat, and H. Hondermarck (2001). Proteomic analysis reveals that 14-3-3 ? is down-regulated in human breast cancer cells. Cancer Res. 61:76–80.
S. Harvey, Y. Zhang, F. Landry, C. Miller, and J. W. Smith. (2001). Insights into plasma membrane signature. Physiol. Genomics 5:129–136.
B. Franzen, G. Auer, A. A. Alaiya, E. Eriksson, K. Uryu, T. Hirano, K. Okuzawa, H. Kato, and S. Linder (1996). Assessment of homogeneity in polypeptide expression in breast carcinomas shows widely variable expression in highly malignant tumors. Int. J. Cancer 69:408–414.
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Souchelnytskyi, S. Proteomics in Studies of Signal Transduction in Epithelial Cells. J Mammary Gland Biol Neoplasia 7, 359–371 (2002). https://doi.org/10.1023/A:1024029930563
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DOI: https://doi.org/10.1023/A:1024029930563