Summary
C-myc and c-erbB-2 amplification and/or overexpression as well as total cathepsin-D (CD) concentration have been reported to be associated with poor prognosis in breast cancer. The prognostic significance, however, remains somewhat controversial, partly because of discrepancies among the different methodologies used. We determined the amplification and overexpression of c-myc oncogene in 152 breast cancer patients and examined its prognostic value in relation to c-erbB-2 amplification and overexpression, high concentration of CD (≥ 60 pmol mg–1 protein) and standard clinicopathological prognostic factors of the disease. High CD concentration, as well as c-myc amplification and overexpression, proved to be the best of the new variables examined for prediction of early relapse (ER; before 3 years). After multivariate analysis only CD remained significant, which suggests that the prognostic power of these variables is similar. Using univariate analysis we proved that c-myc amplification and overexpression were highly significant for disease-free survival (DFS) (P = 0.0016 and P = 0.0001 respectively) and overall survival (OS) (P < 0.0001 and P = 0.0095 respectively), although by multivariate analysis c-myc overexpression was statistically significant only for DFS (P = 0.0001) and c-myc amplification only for OS (P = 0.0006). With regard to c-erbB-2, only its overexpression appeared to be significant for DFS and OS, although after multivariate analysis its prognostic power was weaker (P = 0.030 and P = 0.024 respectively). c-myc amplification and overexpression exhibited a tendency for locoregional recurrence (LRR) (P = 0.0024 and P = 0.0075 respectively), however, their prognostic value was lower after multivariate analysis and only CD remained significant.
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References
Alarscon, R, Rupnow, B, Graeber, T, Knox, S & Giaccia, A (1996). Modulation of c-myc activity and apoptosis in vivo. Cancer Res 56: 4315–4319.
Alitalo, K & Schwab, M (1986). Oncogene amplification in tumour cells. Adv Cancer Res 47: 235–281.
Allred, DC, Harvey, JM & Clark, GM (1998). Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11: 155–168.
Ben-Yosef, T, Yanuka, O, Halle, D & Benvenistry, N (1998). Involvement of myc targets in c-myc and N-myc induced human tumours. Oncogene 17: 165–171.
Berns, EMJJ, Klijn, JGM, van Puten, WLJ, van Staveren, IL, Portengen, H & Foekens, JA (1992a). c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Res 52: 1107–1113.
Berns, EMJJ, Klijin, JGM, van Staveren, IL, Portengen, H, Noordegraaf, E & Foekens, JA (1992b). Prevalence of amplification of the oncogenes c-myc, HER2/neu, and int-2 in one thousand human breast tumours: Correlation with steroid receptors. Eur J Cancer 28: 697–700.
Berns, EM, Klijin, JG, Smid, M, van Staveren, IL, Look, MP, van Putten, WL & Foekens, JA (1996). TP53 and MYC gene alterations independently predict poor prognosis in breast cancer patients. Genes Chromosomes Cancer 16: 170–179.
Bland, KI, Konstadoulakis, MM, Vezeridis, MP & Wanebo, HJ (1995). Oncogene protein co-expression: value of Ha-ras, c-myc, c-fos, and p53 as prognostic discriminants for breast carcinoma. Ann Surg 221: 706–720.
Chomczynski, P & Sacchi, N (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159.
Dati, C, Antoniotti, S, Taverna, D, Perroteau, I & De Bortoli, M (1990). Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells. Oncogene 5: 1001–1006.
Dubik, D & Shiu, RPC (1988). Transcriptional regulation of c-myc oncogene expression by oestrogen in hormone-responsive human breast cancer cells. J Biol Chem 263: 12705–12708.
Escot, C, Theillet, C, Lidereau, R, Spyratos, F, Champeme, MH, Gest, J & Callahan, R (1986). Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas. Proc Natl Acad Sci USA 83: 4834–4838.
Feinberg, A & Vogelstein, B (1984). A technique for labelling DNA restriction fragments to a high specific activity. Anal Biochem 137: 66–67.
Ferrandina, G, Scambia, G, Benedetti-Panici, P, Mancuso, S & Messori, A (1997). Relationship between Cathepsin-D content and disease-free survival in node-negative breast cancer patients: a meta-analysis. Br J Cancer 76, (5): 661–666.
Foekens, JA, Berns, EMJJ & Look, MP et al (1996). Prognostic factors in node-negative breast cancer. In:Hormone-Dependent Cancer, Pasqualini JR, Katzenellebogen BS Dekker: New York 217–253.
Garcia, I, Dietrich, PY, Aapro, M, Vauthier, G, Vadas, L & Engel, F (1989). Genetic alteration of c-myc, c-erbB-2 and c-Ha-ras protooncogenes and clinical associations in human breast carcinomas. Cancer Res 49: 6675–6679.
Gasparini, G, Gozza, F & Harris, AL (1992). Evaluating the potential usefulness of new prognostic and predictive indicators in axillary node-negative breast patients. J Natl Cancer Inst 12: 1006–1014.
Guerin, M, Barrois, M & Terrier, M (1988). Overexpression of either c-myc or c-erbB-2 (neu) proto-oncogene in human breast carcinomas: correlation with poor prognosis. Oncogene Res 3: 21–31.
Kaplan, EL & Meier, P (1958). Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481.
Kreipe, H, Feist, H, Fischer, L, Felgner, J, Heidorn, K, Mettler, L & Parwaresch, R (1993). Amplification of c-myc but not of c-erbB-2 is associated with high proliferative capacity in breast cancer. Cancer Res 53: 1956–1961.
Lonn, U, Lonn, S, Nilsson, B & Stenkvist, B (1995). Prognostic value of erb-B2 and myc amplification in breast cancer imprints. Cancer 75: 2681–2687.
Losch, A, Templer, C, Kohlberger, P, Joura, EA, Denk, M, Zajic, B, Breitenecker, G & Kainz, C (1998). Prognostic value of cathepsin-D expression and association with histomorphological subtypes in breast cancer. Br J Cancer 78: 205–209.
Maniatis, T, Fritsch, EF & Sambrock, J (1982). Molecular Cloning: a Laboratory Manual, Cold Spring Harbour Press: New York
McGuire, WL (1991). Breast cancer prognostic factors: evaluation guidelines. J Natl Cancer Inst 83: 154–155.
Miyada, CG & Wallace, RB (1987). Oligonucleotide hybridization techniques. Methods in enzymol 154: 94–107.
Nass, SJ & Dickson, RB (1997). Defining a role for c-myc in breast tumorigenesis. Breast Cancer Res Treat 44: 1–22.
Osborne, CK (1992). Prognostic factors for breast cancer: have they met their promise?. J Clin Oncol 10: 679–682.
Pavelic, ZP, Pavelic, L, Lower, EE, Gapany, S, Barker, EA & Preisler, HD (1992). c-myc, c-erbB-2 and Ki-67 expression in normal in breast tissue and in invasive and non invasive breast carcinoma. Cancer Res 52: 2597–2602.
Pertschuk, LP, Feldman, JG, Kim, DS, Nayeri, K, Eisenberg, KB, Carte, AC, Thelmo, WT, Rhong, ZT, Benn, P & Grossman, A (1993). Steroid hormone receptor immunohistochemistry and amplification of c-myc protooncogene. Relationship to disease-free survival in breast cancer. Cancer 71: 162–171.
Pietilainen, T, Lipponen, P, Aaltomaa, S, Eskelinen, M, Kosma, VM & Syrjanen, K (1995). Expression of c-myc proteins in breast cancer as related to established prognostic factors and survival. Anticancer Res 15: 959–964.
Prall, OW, Rogan, EM & Sutherland, RL (1998). Estrogen regulation of cell cycle progression in breast cancer cells. J Steroid Biochem Mol Biol 65: 169–174.
Read, LD, Keith, D Jr, Slamon, DJ & Katzenellebogen, BS (1990). Hormone modulation of HER2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res 50: 3947–3951.
Rochefort, H (1992). Biological and clinical significance of cathepsin-D in breast cancer. Acta Oncol 31: 125–130.
Roux-Dosseto, M, Romain, S, Dussault, N, Desideri, C, Piana, L & Bonnier, P et al (1992). c-myc gene amplification in selected node-negative breast cancer patients correlates with high rate of early relapse. Eur J Cancer 28A: 1600–1604.
Santos, GF, Scott, GK, Lee, WMF, Liu, E & Benz, C (1988). Estrogen-induced posttranscriptional modulation of c-myc proto-oncogene expression in human breast cancer cells. J Biol Chem 263: 9565–9568.
Scorilas, A, Yotis, J, Gouriotis, D, Keramopoulos, A, Ampela, K, Trangas, T & Talieri, M (1993). Cathepsin-D and c-erbB-2 have an additive prognostic value for breast cancer patients. Anticancer Res 13: 1895–1900.
Scorilas, A, Yotis, J, Stravolemos, K, Gouriotis, D, Keramopoulos, A, Ampela, K, Talieri, M & Trangas, T (1995). c-erbB-2 overexpression may be used as an independent prognostic factor for breast cancer patients. Anticancer Res 15: 1543–1548.
Scorilas, A, Yotis, J, Pateras, CH, Trangas, T & Talieri, M (1999). Predictive value of c-erbB-2 and Cathepsin-D for Greek breast cancer patients using univariate and multivariate analysis. Clinical Cancer Res 5: 815–821.
Sistonen, L, Koskinen, PJ, Lehvaslaiho, H, Lehtola, L, Bravo, R & Alitalo, K (1990). Down regulation of the early genomic growth factor response in neu oncogene transformed cells. Oncogene 5: 815–821.
Sjogren, S, Inganas, M, Lindgren, A, Holmberg, L & Bergh, J (1998). Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 16: 462–469.
Spyratos, F, Maudelonde, T, Brouillet, JP, Brunet, M, De-Fene, A, Andrieu, C, Harene, K, Desplaces, A, Rouesse, J & Rochefort, H (1989). Cathepsin-D: an independent prognostic factor for metastasis of breast cancer. Lancet ii: 1115–1118.
Suen, TC & Hung, MC (1991). c-myc reverses neu-induced transformed morphology by transcriptional repression. Mol Cell Biol 11: 354–362.
Thomas, PS (1980). Hybridization of denatured RNA and small DNA fragments transferred to a high specific activity. Proc Natl Acad Sci USA 77: 5201–5205.
Thor, AD & Yandell, DW (1996). Molecular pathology of breast carcinoma. In:Diseases of the Breast, Harris JR, Lippman ME, Morrow M, Hellman SLippincott-Raven: Philadelphia 221–235.
Tormod, B & Egil, A (1985). Selecting factors: a comparison of discriminant analysis logistic regression and Cox’s regression model using data from the Tromso heart study. Stat Med 4: 413–423.
Van der Burg, B, van Selm-Miltenburg, AJP, de Last, SW & van Zoolen, EJJ (1989). Direct effects of estrogen on c-fos and c-myc protooncogene expression and cellular proliferation in human breast cancer cells. Mol Cell Endocrinol 64: 223–228.
Watson, PH, Singh, R & Hole, AK (1996). Influence of c-myc on the progression of human breast cancer. Curr Top Microbiol Immunol 213: 267–283.
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Scorilas, A., Trangas, T., Yotis, J. et al. Determination of c-myc amplification and overexpression in breast cancer patients: evaluation of its prognostic value against c-erbB-2, cathepsin-D and clinicopathological characteristics using univariate and multivariate analysis. Br J Cancer 81, 1385–1391 (1999). https://doi.org/10.1038/sj.bjc.6693404
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DOI: https://doi.org/10.1038/sj.bjc.6693404
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