Advertisement

Breast Cancer Research and Treatment

, Volume 145, Issue 2, pp 317–330 | Cite as

Prognostic and biological significance of proliferation and HER2 expression in the luminal class of breast cancer

  • Dena A. Jerjees
  • M. Alabdullah
  • Andrew R. Green
  • Alaa Alshareeda
  • R. D. Macmillan
  • Ian O. Ellis
  • Emad A. Rakha
Preclinical study

Abstract

The definition of Luminal-B subclass of breast cancer (BC) varies in literature. In this study, we have compared the proliferation status; assessed using KI67 labeling index (KI67-LI), and HER2-expression in estrogen receptor positive (ER+) BC to assess their impact on the biological and clinical characteristics of luminal-BC. 1547 (73.8 %) well-characterized clinically annotated stage I–III ER + BC were assessed for expression of KI67, HER2 (ASCO guidelines), and a large panel of relevant biomarkers (no = 37). 46.3 % of the cases show high KI67-LI (>13 %) and 8.4 % show HER2+ and both markers are positively associated with younger age, higher tumor grade and poorer outcome. High KI67-LI and HER2+ are associated with upregulation of ER-coactivators and proliferation-related markers and with downregulation of good prognostic markers. High KI67-LI is associated with larger size, advanced stage, and lymphovascular invasion (LVI) and with downregulation of luminal-enriched and DNA-damage repair markers. In contrast, HER2+ is associated with upregulation of ER-regulated proteins and E-cadherin. When analysis is restricted to high KI67-LI subgroup, HER2+ shows an association with upregulation of differentiation-associated proteins and E-cadherin. Conversely, within HER2+ class, high KI67-LI maintains its association with downregulation of differentiation-associated/luminal-enriched proteins. Outcome analyses indicate that both markers are independently associated with shorter survival but HER2+ is associated with a worse outcome. Although both are associated with high proliferation and poor prognosis within ER + BC, HER2+ is less frequent than high KI67-LI. Unlike KI67, HER2 seems to independently drive the aggressive behavior of ER+ tumors without downregulation of luminal proteins.

Keywords

Breast carcinoma Molecular classes Immunohistochemistry HER2 KI67 

Notes

Acknowledgements

Dena A Jerjees is funded by the higher committee of educational development in Iraq.

Conflicts of interest

None.

Ethical standards

This study was approved by the Nottingham Research Ethics Committee.

References

  1. 1.
    Anderson E (2002) The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 4(5):197–201PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Clarke RB, Anderson E, Howell A (2004) Steroid receptors in human breast cancer. Trends Endocrinol Metab 15(7):316–323PubMedCrossRefGoogle Scholar
  3. 3.
    Mosselman S, Polman J, Dijkema R (1996) ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett 392(1):49–53PubMedCrossRefGoogle Scholar
  4. 4.
    Ctsu RI (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717CrossRefGoogle Scholar
  5. 5.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752PubMedCrossRefGoogle Scholar
  6. 6.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100(14):8418–8423PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Badve S, Turbin D, Thorat MA, Morimiya A, Nielsen TO, Perou CM, Dunn S, Huntsman DG, Nakshatri H (2007) FOXA1 expression in breast cancer–correlation with luminal subtype A and survival. Clin Cancer Res 13(15):4415–4421PubMedCrossRefGoogle Scholar
  10. 10.
    Matos I, Dufloth R, Alvarenga M, Zeferino LC, Schmitt F (2005) p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 447(4):688–694PubMedCrossRefGoogle Scholar
  11. 11.
    Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502PubMedCrossRefGoogle Scholar
  12. 12.
    Guiu S, Michiels S, Andre F, Cortes J, Denkert C, Di Leo A, Hennessy BT, Sorlie T, Sotiriou C, Turner N et al (2012) Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann Oncol 23(12):2997–3006PubMedCrossRefGoogle Scholar
  13. 13.
    Hugh J, Hanson J, Cheang MCU, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M et al (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Bhargava R, Dabbs D (2008) Luminal B breast tumors are not HER2 positive. Breast Cancer Res 10(5):404PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SAW, Wong J, Allred DC, Clark GM, Schiff R (2003) Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95(5):353–361PubMedCrossRefGoogle Scholar
  17. 17.
    Viale G, Regan MM, Mastropasqua MG, Maffini F, Maiorano E, Colleoni M, Price KN, Golouh R, Perin T, Brown R (2008) Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Natl Cancer Inst 100(3):207–212PubMedCrossRefGoogle Scholar
  18. 18.
    Urruticoechea A, Smith IE, Dowsett M (2005) Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23(28):7212–7220PubMedCrossRefGoogle Scholar
  19. 19.
    Liu S, Edgerton SM, Moore DH, Thor AD (2001) Measures of cell turnover (proliferation and apoptosis) and their association with survival in breast cancer. Clin Cancer Res 7(6):1716–1723PubMedGoogle Scholar
  20. 20.
    Spyratos F, Ferrero-Poüs M, Trassard M, Hacene K, Phillips E, Tubiana-Hulin M, Le Doussal V (2002) Correlation between MIB-1 and other proliferation markers. Cancer 94(8):2151–2159PubMedCrossRefGoogle Scholar
  21. 21.
    Brown RW, Allred C, Clark GM, Osborne CK, Hilsenbeck SG (1996) Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 2(3):585–592PubMedGoogle Scholar
  22. 22.
    Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22(3):207–219PubMedCrossRefGoogle Scholar
  23. 23.
    Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ, Robertson JFR, Blamey R, Gee J, Nicholson RI et al (2008) Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur J Cancer 44(1):73–83PubMedCrossRefGoogle Scholar
  24. 24.
    Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rakha EA, Elsheikh SE, Aleskandarany MA, Habashi HO, Green AR, Powe DG, El-Sayed ME, Benhasouna A, Brunet JS, Akslen LA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15(7):2302–2310PubMedCrossRefGoogle Scholar
  26. 26.
    Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO (2008) Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39(6):857–865PubMedCrossRefGoogle Scholar
  27. 27.
    Habashy HO, Rakha EA, Ellis IO, Powe DG (2013) The oestrogen receptor coactivator CARM1 has an oncogenic effect and is associated with poor prognosis in breast cancer. Breast Cancer Res Treat 140(2):307–316PubMedCrossRefGoogle Scholar
  28. 28.
    Alshareeda AT, Negm OH, Albarakati N, Green AR, Nolan C, Sultana R, Madhusudan S, Benhasouna A, Tighe P, Ellis IO et al (2013) Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer. Breast Cancer Res Treat 139(2):301–310PubMedCrossRefGoogle Scholar
  29. 29.
    García-Caballero T, Grabau D, Green AR, Gregory J, Schad A, Kohlwes E, Ellis IO, Watts S, Mollerup J (2010) Determination of HER2 amplification in primary breast cancer using dual-colour chromogenic in situ hybridization is comparable to fluorescence in situ hybridization: a European multicentre study involving 168 specimens. Histopathology 56(4):472–480PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350PubMedCrossRefGoogle Scholar
  31. 31.
    Rakha EA, El-Sayed ME, Green AR, Lee AHS, Robertson JF, Ellis IO (2006) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32CrossRefGoogle Scholar
  32. 32.
    Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van De Rijn M, Jeffrey SS (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98(19):10869PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Sørlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100(14):8418PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Draghici S, Khatri P, Eklund AC, Szallasi Z (2006) Reliability and reproducibility issues in DNA microarray measurements. Trends Genet 22(2):101–109PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, Wu J, Carey LA, Perou CM (2006) Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol 24(11):1656–1664PubMedCrossRefGoogle Scholar
  36. 36.
    Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B et al (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 98(4):262–272PubMedCrossRefGoogle Scholar
  37. 37.
    Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Aleskandarany MA, Green AR, Benhasouna AA, Barros FF, Neal K, Reis-Filho JS, Ellis IO, Rakha EA (2012) Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer. Breast Cancer Res 14(1):R3PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Ihemelandu CU, Leffall LSD, Dewitty RL, Naab TJ, Mezghebe HM, Makambi KH, Adams-Campbell L, Frederick WA (2007) Molecular breast cancer subtypes in premenopausal African-American women, tumor biologic factors and clinical outcome. Ann Surg Oncol 14(10):2994–3003PubMedCrossRefGoogle Scholar
  40. 40.
    Kurebayashi J, Moriya T, Ishida T, Hirakawa H, Kurosumi M, Akiyama F, Kinoshita T, Takei H, Takahashi K, Ikeda M (2007) The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. Breast 16:72–77CrossRefGoogle Scholar
  41. 41.
    Onitilo AA, Engel JM, Greenlee RT, Mukesh BN (2009) Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 7(1–2):4PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Hu Z, Fan C, Oh D, Marron J, He X, Qaqish B, Livasy C, Carey L, Reynolds E, Dressler L (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genom 7(1):96CrossRefGoogle Scholar
  43. 43.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013PubMedCrossRefGoogle Scholar
  44. 44.
    Staaf J, Ringnér M, Vallon-Christersson J, Jönsson G, Bendahl PO, Holm K, Arason A, Gunnarsson H, Hegardt C, Agnarsson BA (2010) Identification of subtypes in human epidermal growth factor receptor 2–positive breast cancer reveals a gene signature prognostic of outcome. J Clin Oncol 28(11):1813–1820PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Dena A. Jerjees
    • 1
    • 2
  • M. Alabdullah
    • 3
  • Andrew R. Green
    • 1
  • Alaa Alshareeda
    • 1
  • R. D. Macmillan
    • 4
  • Ian O. Ellis
    • 1
  • Emad A. Rakha
    • 1
  1. 1.Department of HistopathologyUniversity of Nottingham and Nottingham University Hospitals NHS TrustNottinghamUK
  2. 2.Department of PathologyMosul School of MedicineMosulIraq
  3. 3.Department of SurgerySchool of MedicineMosulIraq
  4. 4.Breast InstituteCity HospitalNottinghamUK

Personalised recommendations