Clinical and Experimental Medicine

, Volume 12, Issue 4, pp 217–223 | Cite as

C-myc as a predictive marker for chemotherapy in metastatic breast cancer

  • Nataša Todorović-Raković
  • Zora Nešković-Konstantinović
  • Dragica Nikolić-Vukosavljević
Original Article

Abstract

C-myc is considered to have an important role in cancerogenesis and tumor progression. The aim of this study was to evaluate a possible significance of c-myc amplification as a clinically useful prognostic/predictive parameter in metastatic breast cancer (MBC). Eighty-seven MBC patients with known clinicopathological parameters were included in the study, at the time of diagnosis of metastatic disease. In metastatic setting, 52% of patients received CMF, 34% received FAC, and 32% received hormonal therapy (tamoxifen). C-myc amplification was analyzed by chromogenic in situ hybridization, according to the manufacturer’s instructions. C-myc amplification was detected in 26% cases and showed a strong correlation with ER status, stage of disease (initial) and existence of distance metastasis. There was no statistically significant difference in MBC (post-relapse) survival between c-myc-nonamplified and c-myc-amplified subgroups regardless of or regarding the treatment. However, correlation was found between c-myc status and individual patient’s outcomes. Patients with c-myc amplification treated with chemotherapy (CMF and FAC) had clinical benefit (complete remission, partial remission or stable disease) in contrast to patients without amplification. Lack of significant difference in MBC (post-relapse) survival according to c-myc status could be due to a better response of patients to appropriate treatment (chemotherapy). It is possible that negative prognostic impact of c-myc amplification is masked with increased responsiveness to chemotherapy.

Keywords

C-myc Amplification Metastatic breast cancer Chemotherapy 

Notes

Acknowledgments

This work was supported by Grant No. 175068 “Molecular biomarkers of breast cancer and changes of their significance depending on the follow-up of the disease” from the Ministry of Science and Environment Protection of Republic of Serbia.

Conflict of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Dang CV (1999) C-myc target genes involved in cell growth, apoptosis and metabolism. Mol Cell Biol 19:1–11PubMedGoogle Scholar
  2. 2.
    Cappellen D, Schlange T, Bauer M, Maurer M, Hynes NE (2007) Novel c-MYC target genes mediate differential effects on cell proliferation and migration. EMBO Rep 8:70–76PubMedCrossRefGoogle Scholar
  3. 3.
    Lutz W, Leon J, Eilers M (2002) Contributions of Myc to tumorigenesis. Biochim Biophys Acta 1602:61–71Google Scholar
  4. 4.
    Liao DJ, Dickson RB (2000) C-myc in breast cancer. Endocr Relat Cancer 7:143–164PubMedCrossRefGoogle Scholar
  5. 5.
    Berns EM, Foekens JA, van Putten WL, van Staveren IL, Portengen H, de Koning WC, Klijn JG (1992) Prognostic factors in human primary breast cancer: comparison of c-myc and HER2/neu amplification. J Steroid Biochem Mol Biol 43:13–19PubMedCrossRefGoogle Scholar
  6. 6.
    Berns EM, Kiijn JG, van Starveren IL, Portengen H, de Koning WC, Foekens JA (1992) Prevalence of amplification of the oncogene c-myc, HER2/neu, and int-2 in one thousand human breast tumors: correlation with steroid receptor status. Eur J Cancer 28:697–700PubMedCrossRefGoogle Scholar
  7. 7.
    Scorilas A, Trangas T, Yotis J, Pateras C, Talieri M (1999) 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 81:1385–1391PubMedCrossRefGoogle Scholar
  8. 8.
    Rummukainen JK, Salminen T, Lundin J, Kytölä S, Joensuu H, Isola JJ (2001) Amplification of c-myc by fluorescence in situ hybridization in a population-based breast cancer tissue array. Mod Pathol 14:1030–1035PubMedCrossRefGoogle Scholar
  9. 9.
    Hermeking H (2003) The Myc oncogene as a cancer drug target. Curr Cancer Drug Targets 3:163–175PubMedCrossRefGoogle Scholar
  10. 10.
    Todorović-Raković N, Jovanović D, Nesković-Konstantinović Z, Nikolić-Vukosavljević D (2007) Prognostic value of HER2 gene amplification detected by chromogenic in situ hybridization (CISH) in metastatic breast cancer. Exp Mol Pathol 82:262–268PubMedCrossRefGoogle Scholar
  11. 11.
    Todorović-Raković N, Nesković-Konstantinović Z, Nikolić-Vukosavljević D (2009) Metastatic breast cancer survival according to HER2 and Topo2a gene status. Dis Markers 26:171–180PubMedGoogle Scholar
  12. 12.
    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. PNAS 83:4834–4838PubMedCrossRefGoogle Scholar
  13. 13.
    Bonilla M, Ramirez M, Lopez-Cueto J, Gariglio P (1988) In vivo amplification and rearrangement of c-myc oncogene in human breast tumors. J Natl Cancer Inst 80:665–671PubMedCrossRefGoogle Scholar
  14. 14.
    Harada Y, Katagiri T, Ito I, Sakamoto G, Kasumi F, Nakamura Y, Emi M (1994) Genetic studies of 457 breast cancers. Clinocopathological parameters compared with genetic alterations. Cancer 74:2281–2286PubMedCrossRefGoogle Scholar
  15. 15.
    Contegiacomo A, Pizzi C, De Marchis L, Alimandi M, Delrio P, Di Palma E et al (1995) High cell kinetics is associated with amplification of the int-1, bcl1, myc and erbB-2 proto-oncogenes and loss of heterozygosity at the DF3 locus in primary breast cancer. Int J Cancer 61:1–6PubMedCrossRefGoogle Scholar
  16. 16.
    Ito I, Yoshimoto M, Iwase T, Watanabe H, Katagiri T, Harada Y et al (1995) Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer. Br J Cancer 71:438–441PubMedCrossRefGoogle Scholar
  17. 17.
    Adnane J, Gaudray P, Simon MP, Simony-Lafontaine J, Jeanteur P, Theillet C (1989) Proto-oncogene amplification and human breast cancer phenotype. Oncogene 4:1389–1395PubMedGoogle Scholar
  18. 18.
    Mizukami Y, Nonomura A, Noguchi M, Taniya T, Koyasaki N, Saito Y et al (1991) Immunohistochemical study of oncogene product ras 21, c-myc and growth factor EGF in breast carcinomas. Anticancer Res 11:1485–1494PubMedGoogle Scholar
  19. 19.
    Courjal F, Theillet C (1997) Comparative genomic hybridization analysis of breast tumors with predetermined profiles of DNA amplification. Cancer Res 57:4368–4377PubMedGoogle Scholar
  20. 20.
    Cuny M, Kramer A, Courjal F, Johannsdottir V, Iacopetta B, Fontaine H et al (2000) Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. Cancer Res 60:1077–1083PubMedGoogle Scholar
  21. 21.
    Persons DL, Borelli KA, Hsu PH (1997) Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescent in situ hybridization. Mod Pathol 10:720–727PubMedGoogle Scholar
  22. 22.
    Kreipe H, Feist H, Fischer L, Feigner J, Heidorn K, Mettler L, Parwarech R (1993) Amplification of c-myc but not of c-erbB-2 is associated with high proliferative capacity in breast cancer. Cancer Res 53:1956–1961PubMedGoogle Scholar
  23. 23.
    Deming SL, Nass SJ, Dickson RB, Trock JB (2000) C-myc amplification in breast cancer: a meta analysis of its occurrence and prognostic relevance. Br J Cancer 83(12):1688–1695PubMedCrossRefGoogle Scholar
  24. 24.
    Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, Brown M, Brown PH (2011) Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol Endocrinol 25:1527–1538PubMedCrossRefGoogle Scholar
  25. 25.
    Wang Y, Liu S, Zhang G, Zhou C, Zhu H, Zhou X et al (2005) Knockdown of c-myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo. Breast Cancer Res 7:R220–R228PubMedCrossRefGoogle Scholar
  26. 26.
    Dubik D, Shiu RP (1988) Transcriptional regulation of c-myc oncogene expression by estrogen in hormone-responsive human breast cancer cells. J Biol Chem 263:12705–12708PubMedGoogle Scholar
  27. 27.
    Bernstein PL, Herrick DJ, Prokipcak RD, Ross J (1992) Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev 6:642–654PubMedCrossRefGoogle Scholar
  28. 28.
    Wong MSJ, Murphy LC (1991) Differential regulation of c-myc by progestins and antiestrogens in T-47D human breast cancer cells. J Steroid Biochem Mol Biol 39:39–44PubMedCrossRefGoogle Scholar
  29. 29.
    Musgrove EA, Lee CS, Sutherland RL (1991) Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes. Mol Cell Biol 11(10):5032–5043PubMedGoogle Scholar
  30. 30.
    Robarius-Mandag EC, Bosch CA, Kristel PM, Hart AAM, Farieyte IF, Nederlof PM et al (2003) Association of c/myc amplification with progression from the in situ to the invasive stage in c-myc amplified breast carcinomas. J Pathol 201:75–82CrossRefGoogle Scholar
  31. 31.
    Rodriguez-Pinilla SM, Jones RL, Lambros MBK, Arriola E, Savage K, James M et al (2007) MYC amplification in breast cancer: a chromogenic in situ hybridization study. J Clin Pathol 60:1017–1023PubMedCrossRefGoogle Scholar
  32. 32.
    Aulmann S, Adler N, Rom J, Helmchen B, Schirmacher P, Sinn HP (2006) C-myc amplifications in primary breast carcinomas and their local recurrences. J Clin Pathol 59:424–428PubMedCrossRefGoogle Scholar
  33. 33.
    Wolfer A, Wittner BS, Irimia D, Flavin RJ, Lupien M, Gunawardane RN et al (2009) MYC regulation of a “poor-prognosis” metastatic cancer cell state. PNAS 107:3698–3703CrossRefGoogle Scholar
  34. 34.
    Borg A, Baldetorp B, Ferno M, Olsson H, Sigurdsson H (1992) C-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int J Cancer 51:687–691PubMedCrossRefGoogle Scholar
  35. 35.
    Roux-Dosseto M, Romain S, Dissault N, Desiders 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 2:1600–1604CrossRefGoogle Scholar
  36. 36.
    Guerin M, Barrois M, Terrier MJ, Spielmann M, Riou G (1988) Overexpression of either c-myc or c-erbB2 protooncogenes in human breast carcinomas: correlation with poor prognosis. Oncogene Res 3:21–31PubMedGoogle Scholar
  37. 37.
    Mimori K, Mori M, Shiraishi T, Tanaka S, Haraguchi M, Ueo H et al (1998) Expression of ornithine decarboxylase mRNA and c-myc mRNA in breast tumors. Int J Oncol 12:597–601PubMedGoogle Scholar
  38. 38.
    Mizukami Y, Nonomura A, Noguchi M, Taniya T, Koyasaki N, Saito Y et al (1991) Immunohistochemical study of oncogene product ras 21, c-myc and growth factor EGF in breast carcinomas. Anticancer Res 11:1485–1494PubMedGoogle Scholar
  39. 39.
    Gutman M, Ravia Y, Assaf D, Yamamoto T, Rozin R, Shifon Y (1989) Amplification of c-myc and c-erbB2 proto-oncogenes in human solid tumors: frequency and clinical significance. Int J Cancer 44:802–805PubMedCrossRefGoogle Scholar
  40. 40.
    Bieche I, Laurendau I, Tozlu S, Olivi M, Vidaud D, Lidereau R et al (1999) Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Res 59:2759–2765PubMedGoogle Scholar
  41. 41.
    Pietilainen T, Lipponen P, Aaltuman 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 15:959–964PubMedGoogle Scholar
  42. 42.
    Yasojima H, Shimomura A, Naoi Y, Kishi K, Baba Y, Shimazu K et al (2011) Association between c-myc amplification and pathological complete response to neoadjuvant chemotherapy in breast cancer. Eur J Cancer 12:1779–1788CrossRefGoogle Scholar
  43. 43.
    Augenlicht LH, Wadler S, Corner G, Richards C, Ryan I, Multani AS et al (1997) Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: a frequent p53-independent mutation associated with improved outcome in a randomized multi-institutional trial. Cancer Res 57:1769–1775PubMedGoogle Scholar
  44. 44.
    Iba T, Kigawa J, Kanantori Y, Itamochi H, Oishi T, Simada M et al (2006) Expression of the e c-myc gene as a predictor of chemotherapy response and a prognostic factor in patients with ovarian cancer. Cancer Sci 95:418–423CrossRefGoogle Scholar
  45. 45.
    Robertson JFR, Willsher PC, Cheung KL et al (1997) The clinical relevance of static disease (no change) category for 6 months on endocrine therapy in patients with breast cancer. Eur J Cancer 33:1774–1779PubMedCrossRefGoogle Scholar
  46. 46.
    Schlotter CM, Vogt U, Bosse U, Mersch B, Wassmann K (2003) C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer. Breast Cancer Res 5:R30–R36PubMedCrossRefGoogle Scholar
  47. 47.
    Petrelli EF, Cabiddu M, Cazzaniga ME et al (2008) Targeted therapies for the treatment of breast cancer in the post-trastuzumab era. Oncologist 13:373–381PubMedCrossRefGoogle Scholar
  48. 48.
    Biliran H, Banerjee S, Thakur A et al (2007) C-Myc–induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-κB activity in pancreatic cancer cells. Clin Cancer Res 13:2811PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nataša Todorović-Raković
    • 1
  • Zora Nešković-Konstantinović
    • 2
  • Dragica Nikolić-Vukosavljević
    • 1
  1. 1.Department of Experimental OncologyInstitute for Oncology and Radiology of SerbiaBelgradeSerbia
  2. 2.Department of Clinical OncologyInstitute for Oncology and Radiology of SerbiaBelgradeSerbia

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