Breast Cancer Research and Treatment

, Volume 74, Issue 1, pp 25–31

C-myc oncogene amplification in ductal carcinoma in situ of the breast

  • Sebastian Aulmann
  • Martin Bentz
  • Hans Peter Sinn


The c-myc oncogene is frequently activated in invasive breast cancer and has been associated with high nuclear grade, lymph node metastasis and poorer disease outcome. We have examined c-myc oncogene amplification using fluorescence in situ hybridization in a series of 96 pure DCIS. Additionally we assessed amplification and expression of the Her2 and bcl-2 oncogenes. The findings were compared with clinicopathological data, Ki-67 proliferative index and hormone receptor status. We observed c-myc oncogene amplification in 19 tumours (20%). These cases were significantly associated with an average of 38% higher proliferative activity (p = 0.045), a 43% larger tumour size (p = 0.029) and the otherwise rare micropapillary subtype (p = 0.0005). Concluding the c-myc oncogene appears to be involved in the development of a more aggressive phenotype of DCIS.

bcl-2 c-myc DCIS FISH Her2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Amati B, Alevizopoulos K, Vlach J: Myc and the cell cycle. Front Biosci 3: D250–D268, 1998Google Scholar
  2. 2.
    Barrett JF, Lewis BC, Hoang AT, Alvarez RJJ, Dang CV: Cyclin a links c-myc to adhesion-independent cell proliferation. J Biol Chem 270: 15923–15925, 1995Google Scholar
  3. 3.
    Barth TFE, Döhner H, Werner CA, Stilgenbauer S, Schlotter M, Pawlita M, Lichter P, Möller P, Bentz M: Characteristic pattern of chromosomal gains and losses in primary large Bcell lymphomas of the gastrointestinal tract. Blood 11: 4321–4330, 1998Google Scholar
  4. 4.
    Berns EMJJ, Foekens JA, Putten WLJV, Staveren ILV, Portengen H, Koning WCHD, Klijn JGM: Prognostic factors in human primary breast cancer: comparison of c-myc and HER2/neu amplification. J Steroid Biochem Mol Biol 43: 13–19, 1992Google Scholar
  5. 5.
    Berns EMJJ, Klijn JG, Smid M, Staveren ILV, Look MP, Putten WLV, Foekens JA: TP53 and MYC gene alterations independently predict poor prognosis in breast cancer patients. Genes Chrom Cancer 16: 170–179, 1996Google Scholar
  6. 6.
    Bieche I, Laurendeau I, Tozlu S, Olivi M, Vidaud D, Lidereau R, Vidaud M: Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Res 59: 2759–2765, 1999aGoogle Scholar
  7. 7.
    Bieche I, Onody P, Laurendeau I, Olivi M, Vidaud D, Lidereau R, Vidaud M: Real-time reverse transcription-PCR assay for future management of erbB2-based clinical applications. Clin Chem 45: 1148–1156, 1999bGoogle Scholar
  8. 8.
    Blackwell TK, Kretzner L, Blackwood EM, Wintraub RNE end H: Sequence specific DNA binding by the c-myc protein. Science 250: 1149–1151, 1990Google Scholar
  9. 9.
    Blackwood EM, Eisenmann RN: Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA binding complex with Myc. Science 251: 1211–1217, 1991Google Scholar
  10. 10.
    Borg Å, Baldetorp B, Fernö M, Olsson H, Sigurdsson H: C-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int J Cancer 51: 687–691, 1992Google Scholar
  11. 11.
    Cardiff RD, Sinn E, Muller W, Leder P: Transgenic oncogene mice. Tumor phenotype predicts genotype. Am J Pathol 139: 495–501, 1991Google Scholar
  12. 12.
    Chan KC, Knox WF, Sinha G, Gandhi A, Barr L, Baildam AD, Bundred NJ: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91: 9–16, 2001Google Scholar
  13. 13.
    Consensus conference on the classification of ductal carcinoma in situ. Cancer 80: 1798–1802, 1997Google Scholar
  14. 14.
    Cory S, Vaux DL, Strasser A, Harris AW, Adams JM: Insights from bcl-2 and myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. Cancer Res 59 (suppl): 1685s–1692s, 1999Google Scholar
  15. 15.
    Dang CV: C-myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19: 1–11, 1999Google Scholar
  16. 16.
    D´ Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD, Chodosh LA: C-myc induces mammary tumorigenesis by means of a preferred pathway involving spontaneous kras2 mutations. Nature Med 7: 235–239, 2001Google Scholar
  17. 17.
    Deming SL, Nass SJ, Dickson RB, Trock BJ: C-myc amplification in breast cancer: a meta-analysis of its occurrence andprognostic relevance. Br J Cancer 83: 1688–1695, 2000Google Scholar
  18. 18.
    Dublin EA, Millis RR, Smith P, Bobrow LG: Minimal breast cancer: evaluation of histology and biological marker expression. Br J Cancer 80: 1608–1616, bjoc.1999.0570, 1999Google Scholar
  19. 19.
    Facchini LM, Penn LZ: The molecular role of myc in growth and transformation: recent discoveries lead to new insights. FASEB J 12: 633–651, 1998Google Scholar
  20. 20.
    Gaffey MJ, Frierson HF, Williams ME: Chromosome 11q13, c-erbB-2 and c-myc amplifications in invasive breast carcinoma: clinicopathologic correlations. Mod Pathol 6: 654–659, 1993Google Scholar
  21. 21.
    Guo QM, Malek RL, Kim S, Chiao C, He M, Ruffy M, Sanka K, Lee NH, Dang CV, Liu ET: Identification of c-myc responsive genes using rat cDNA microarray. Cancer Res 60: 5922–5928, 2000Google Scholar
  22. 22.
    Jager R, Herzer U, Schenkel J, Weiher H: Overexpression of bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene 15: 1787–1795, 1997Google Scholar
  23. 23.
    Joos S, Falk M, Lichter P, Haluska FG, Henglein B, Lenoir GM, Bornkamm GW: Variable breakpoints in burkitt lymphoma cells with chromosomal t(8;14) translocation separate c-myc and the IgH locus up to several hundred kb. Hum Mol Genet 1: 625–632, 1992Google Scholar
  24. 24.
    Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP: Tissue microarrays for high-throuput molecular profiling of tumor specimens. Nat Med 4: 844–847, 1998Google Scholar
  25. 25.
    Kreipe H, Feist H, Felgner J, Heidorn K, Mettler L, Parwaresch R: Amplification of c-myc but not of c-erbB-2 is associated with high proliferative capacity in breast cancer. Cancer Res 53: 1956–1961, 1993Google Scholar
  26. 26.
    Lichter P, Bentz M, Joos S: Detection of chromosomal aberratins by means of molecular cytogenetics: painting of chromosomes and chromosomal subregions and comparative genomic hybridization. Meth Enzymol 254: 334–359, 1995Google Scholar
  27. 27.
    McCormack SJ, Weaver Z, Deming S, Natarajan G, Torri J, Johnson MD, Liyanage M, Ried T, Dickson RB: Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability. Oncogene 16: 2755–2766, 1998Google Scholar
  28. 28.
    Pegram MD, Slamon DJ: Combination Therapy with Trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol 26 (suppl 12) 89–95: 1999Google Scholar
  29. 29.
    Persons DL, Borelli KA, Hsu PH: Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescence in situ hybridization. Mod Pathol 10: 720–727, 1997Google Scholar
  30. 30.
    R-Project: The R Project for statistical computing. http://www. Scholar
  31. 31.
    Remmele W, Dietz M, Schmidt F, Schiketanz KH: Relation of elastosis to biochemical and immunohistochemical steroid receptor findings, Ki-67 and epidermal growth factor receptor (EGFR) immunostaining in invasive ductal breast cancer. Virchows Arch 422: 319–326, 1993Google Scholar
  32. 32.
    Schwartz GF, Patchefsky AS, Finkelstein SD, Sohn SH, Prestipino A, Feig SA, Singer JS: Nonpalpable in situ ductal carcinoma of the breast. Predictors of multicentricity and microinvasion and implications for treatment. Arch Surg 124: 29–32, 1989Google Scholar
  33. 33.
    Scorilas A, Trangas T, Yotis J, Pateras C, Talieri M: 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, 1999Google Scholar
  34. 34.
    Silverstein MJ, Lagios MD, Groshen S, Waisman JR, Lewinsky BS, Martino S, Gamagami P, Colburn WJ: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340: 1455–1461, 1999Google Scholar
  35. 35.
    Sinn HP, Anton HW, Magener A, von Fournier D, Bastert G, Otto HF: Extensive and predominant in situ component in breast carcinoma: their influence on treatment results after breast-conserving therapy. Eur J Cancer 34: 646–653, 1998Google Scholar
  36. 36.
    Soini Y, Mannermaa A, Winqvist R, Kamel D, Poikonen K, Kiviniemi H, Paakko P: Application of fine-needle aspiration to the demonstration of erbb2 and myc expression by in situ hybridization in breast carcinoma. J Histochem Cytochem 42: 795–803, 1994Google Scholar
  37. 37.
    Stewart TA, Pattengale P, Leder P: Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 48: 627–637, 1984Google Scholar
  38. 38.
    Taylor SL, Platt-Higgins A, Sudland PS, Winstanley JHR, Barraclough R: Cytoplasmic staining of c-erbB-2 is not associated with the presence of detectable c-erbB-2 mRNA in breast cancer specimens. Int J Cancer 76: 459–463, 1998Google Scholar
  39. 39.
    Vos CBJ, ter Haar NT, Rosenberg C, Peterse JL, Cleton-Jansen AM, Cornelisse CJ, van de Vijver MJ: Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Br J Cancer 81: 1410–1418, 1999Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Sebastian Aulmann
    • 1
  • Martin Bentz
    • 2
  • Hans Peter Sinn
    • 1
  1. 1.Department of PathologyUniversity of HeidelbergGermany
  2. 2.Department of Internal Medicine IIIUniversity of UlmGermany

Personalised recommendations