Protein expression of B-cell lymphoma gene 6 (BCL-6) in invasive breast cancer is associated with cyclin D1 and hypoxia-inducible factor-1α (HIF-1α)

Article metrics


B-cell lymphoma gene (BCL-6) upregulation contributes to immortalization of mouse embryo fibroblast and primary B cells via upregulation of cyclin D1. As cyclin D1 overexpression is a common phenomenon in different cancers, BCL-6 protein overexpression may not be restricted to lymphomas. In this study, expression of BCL-6 was investigated by immunohistochemistry on paraffin-embedded specimens from 150 breast cancer patients and 10 specimens of normal breast tissue. The results showed BCL-6 overexpression (10% of cells) in 24/150 (16%) breast cancer patients, whereas in normal breast low expression (<1%) of BCL-6 was observed. In linear regression analysis BCL-6 expression was associated with cyclin D1 (r=0.197, P=0.016). Further, in χ2 analyses, BCL-6-positivity was associated with overexpression of p53 (P=0.016), and hypoxia-inducible factor-1α (P<0.001). Involvement of BCL-6 in breast carcinogenesis is further underscored by comparative genomic hybridization analysis that showed gains at the BCL-6 locus (3q27) in 14/86 (16%) breast cancer tissues. The cases with amplification in BCL-6 showed an increased (25%) incidence of BCL-6 protein overexpression. Thus, this study is the first to show that BCL-6 oncogene activation plays a role in cancers other than lymphomas.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1


  1. Bindra RS, Vasselli JR, Stearman R, Linehan WM and Klausner RD . (2002). Cancer Res., 62, 3014–3019.

  2. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, Semenza GL, van Diest PJ and van der Wall E . (2003). Cancer, 97, 1573–1581.

  3. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ and van der Wall E . (2001). J. Natl. Cancer Inst., 93, 309–314.

  4. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E and Keshet E . (1998). Nature, 394, 485–490.

  5. Chang CC, Ye BH, Chaganti RS and Dalla-Favera R . (1996). Proc. Natl. Acad. Sci. USA, 93, 6947–6952.

  6. Dunphy CH, Polski JM, Lance EH and Gardner LJ . (2001). Leuk. Lymphoma, 41, 585–592.

  7. Elston CW and Ellis IO . (1991). Histopathology, 19, 403–410.

  8. Hermsen MA, Baak JP, Meijer GA, Weiss JM, Walboomers JW, Snijders PJ and van Diest PJ . (1998). J. Pathol., 186, 356–362.

  9. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW and Ratcliffe PJ . (2001). Science, 292, 468–472.

  10. de Jong JS, van Diest PJ, Michalides RJ and Baak JP . (1999). Mol. Pathol., 52, 78–83.

  11. Ree HJ, Ohsima K, Aozasa K, Takeuchi K, Kim CW, Yang WI, Huh JY, Lee SS, Ko YH, Kwon MS, Cho EY, Choi YL, Chul RJ, Kikuchi M and Mori S . (2003). Hum. Path., 36, 610–616.

  12. Semenza GL . (2002). Trends Mol. Med., 8, S62–S67.

  13. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP and Staudt LM . (2000). Immunity, 13, 199–212.

  14. Shvarts A, Brummelkamp TR, Scheeren F, Koh E, Daley GQ, Spits H and Bernards R . (2002). Genes Dev., 16, 681–686.

  15. van Diest PJ, Baak JP, Matze-Cok P, Wisse-Brekelmans EC, van Galen CM, Kurver PH, Bellot SM, Fijnheer J, van Gorp LH and Kwee WS . (1992). Hum. Pathol., 23, 603–607.

  16. van Diest PJ, Michalides RJ, Jannink L, van dere Valk P, Peterse HL, de Jong JS, Meijer CJ and Baak JP . (1997). Am. J. Pathol., 150, 705–711.

  17. Ye BH . (2000). Cancer Invest., 18, 356–365.

  18. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, Leung C, Nouri-Shirazi M, Orazi A, Chaganti RS, Rothman P, Stall AM, Pandolfi PP and Dalla-Favera R . (1997). Nat. Genet., 16, 161–170.

  19. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW . (1999). Cancer Res., 59, 5830–5835.

Download references


We are grateful to Dr Mehdi Jiwa from the Medical Center Alkmaar for providing tissue material of patients for CGH and BCL-6 staining. This work was supported by generous research support from the AEGON International Scholarship in Oncology (RB, PvdG, AEG, IH, AS), and in part by the KWF Grant 03-2825 (MAJAH).

Author information

Correspondence to Avi Shvarts.

Rights and permissions

Reprints and Permissions

About this article


  • BCL-6
  • HIF-1α
  • cyclin D1
  • oncogenes
  • breast cancer

Further reading