Skip to main content

Advertisement

SpringerLink
Log in

Apolipoprotein D predicts adverse outcome in women ≥70 years with operable breast cancer

  • Clinical Trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Apolipoprotein D (ApoD) is a lipocalin involved in various cellular processes, including cytoprotection. We retrospectively evaluated its prognostic impact in 272 women (median age 63 (range 21–89) years, with operable breast cancer (Stage I or IIa) treated according to national guidelines, stratified by age and menopausal status, with a median long-term follow-up of 12 years. ApoD, estrogen receptor-alpha (ERα), and progesterone receptor (PR) positivity were determined by quantitative immunohistochemistry in tissue microarrays taken from the invasive front of the tumors and in whole tumor sections. ApoD was expressed in 50% of the tumors. Diffuse nuclear and cytoplasmic (ApoDCN), but not granular cytoplasmic ApoD expression in the invasive front was a detrimental factor for elderly patients over 70 years of age, (n = 83), but not for younger and pre-menopausal patients. ApoDCN expression correlated with lymph node metastases (P = 0.04). Moreover, a correlation between ApoDCN localization and age over 70 years was observed (P = 0.03). In the elderly, ApoDCN positive tumors had both a significantly shorter relapse-free survival (all locations) (P = 0.02) and a decreased breast cancer-specific survival (P < 0.0001). Moreover, the prognostic importance of ApoD was dose dependent (P = 0.002) Multivariate analysis confirmed the prognostic value of ApoDCN. When the elderly patients were stratified by nodal status, ApoD showed prognostic importance only in the node positive patients (n = 30) (HR = 9.6; 95% CI = 2.3–40.4). The potential relevance of ApoD in this increasingly frequent group of breast cancer patients should be further explored.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Veronesi U, Boyle P, Goldhirsch A et al (2005) Breast cancer. Lancet 365:1727–1741

    Article  PubMed  Google Scholar 

  2. Walker RA (2003) Prognostic and predictive factors in breast cancer: an overview. In: Walker RA (ed) Prognostic and predictive factors in breast cancer, Martin Duniz, Taylor & Francis, UK, pp 1–5

    Google Scholar 

  3. Søreide JA, Lea OA, Kvinnsland S (1987) Progesterone binding cyst protein (PBCP) in primary breast cancer: a new prognostic factor? Breast Cancer Res Treat 9:123–128

    Article  PubMed  Google Scholar 

  4. Søreide JA, Lea OA, Anda O et al (1991) Progesterone-binding cyst protein (PBCP) in operable breast cancer: correlations with prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Anticancer Res 11:601–605

    PubMed  Google Scholar 

  5. Diez-Itza I, Vizoso F, Merino AM et al (1994) Expression and prognostic significance of apolipoprotein D in breast cancer. Am J Pathol 144:310–320

    PubMed  CAS  Google Scholar 

  6. Flower DR (2000) The lipocalin protein family: structural and sequence overview. Biochem Biophys Acta 1482:9–24

    PubMed  CAS  Google Scholar 

  7. Ayrault Jarrier M, Levy G, Polonovski J (1963) Study of humanserum alpha-lipoproteins by immunoelectrophoresis. Bull Soc Chim Biol (Paris) 45:703–713

    CAS  Google Scholar 

  8. Pearlman WH, Gueriguian JL, Sawyer ME (1973) A specific progesterone-binding component of human breast cyst fluid. J Biol Chem 248:5736–5741

    PubMed  CAS  Google Scholar 

  9. Haagensen DE Jr, Mazoujian G, Holder WD Jr et al (1977) Evaluation of a breast cyst fluid protein detectable in the plasma of breast carcinoma patients. Ann Surg 185:279–285

    PubMed  Google Scholar 

  10. Lea OA, Kvinnsland S, Thorsen T (1987) Progesterone-binding cyst protein in human breast tumor cytosol. Cancer Res 47:6189–6192

    PubMed  CAS  Google Scholar 

  11. Balbin M, Freije JM, Fueyo A et al (1990) Apolipoprotein D is the major protein component in cyst fluid from women with human breast gross cystic disease. Biochem J 271:803–807

    PubMed  CAS  Google Scholar 

  12. Rassart E, Bedirian A, Do Carmo S et al (2000) Apolipoprotein D. Biochim Biophys Acta 1482:185–198

    PubMed  CAS  Google Scholar 

  13. Online Mendelinan Inheritance in Man™ (OMIM™), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), World Wide Web URL:/http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=107740. Cited February 7, 2008

  14. Morais Cabral JH, Atkins GL, Sanchez LM et al (1995) Arachidonic acid binds to apolipoprotein D: implications for the protein's function. FEBS Lett 366:53–56

    Article  PubMed  CAS  Google Scholar 

  15. Romano M, Claria J (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 17:1986–1995

    Article  PubMed  CAS  Google Scholar 

  16. Simard J, de Launoit Y, Haagensen DE et al (1992) Additive stimulatory action of glucocorticoids and androgens on basal and estrogen-repressed apolipoprotein-D messenger ribonucleic acid levels and secretion in human breast cancer cells. Endocrinology 130:1115–1121

    Article  PubMed  CAS  Google Scholar 

  17. Lea OA (1988) Binding properties of progesterone-binding Cyst protein, PBCP. Steroids 52:337–338

    Article  PubMed  CAS  Google Scholar 

  18. Harding C, Osundeko O, Tetlow L et al (2000) Hormonally-regulated proteins in breast secretions are markers of target organ sensitivity. Br J Cancer 82:354–360

    Article  PubMed  CAS  Google Scholar 

  19. Do Carmo S, Levros LC Jr, Rassart E (2007) Modulation of apolipoprotein D expression and translocation under specific stress conditions. Biochim Biophys Acta 1773:954–969

    Article  PubMed  CAS  Google Scholar 

  20. Thomas EA, Copolov DL, Sutcliffe JG (2003) From pharmacotherapy to pathophysiology: emerging mechanisms of apolipoprotein D in psychiatric disorders. Curr Mol Med 3:408–418

    Article  PubMed  CAS  Google Scholar 

  21. West RB, Nuyten DS, Subramanian S et al (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3:e187

    Article  PubMed  CAS  Google Scholar 

  22. Søiland H, Søreide K, Janssen EAM et al (2007) Emerging concepts of apolipoprotein D with possible implications for breast cancer. Cell Oncol 29:195–209

    PubMed  Google Scholar 

  23. Søiland H, Skaland I, Janssen EAM et al (2008) Comparison of Apolipoprotein D determination methods in breast cancer. Anticancer Res 28:673–680

    Google Scholar 

  24. Søreide JA, Lea OA, Varhaug JE et al (1992) Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Eur J Surg Oncol 18:112–118

    PubMed  Google Scholar 

  25. Sobin LH, Witterkind C (2002) Breast tumors. In: TNM classifications of malignant tumors, 6th edn. International Union Against Cancer (UICC). John Wiley & Sons, Hoboken, New Jersey, pp 131–142

  26. Tavassoli FA, Devilee P (2003) Pathology and genetics of tumours of the breast and female genital organs. In: World Health Organization classification of tumours. IARC Press, Lyon, pp 9–112

  27. Baak JP, van Diest PJ, Voorhorst FJ et al (2007) The prognostic value of proliferation in lymph-node-negative breast cancer patients is age dependent. Eur J Cancer 43:527–535

    Google Scholar 

  28. Crivellari D, Aapro M, Leonard R et al (2007) Breast cancer in the elderly. J Clin Oncol 25:1882–1890

    Article  PubMed  Google Scholar 

  29. Baak JP, van Diest PJ, Voorhorst FJ et al (2005) Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. J Clin Oncol 23:5993–6001

    Article  PubMed  Google Scholar 

  30. Kallioniemi OP, Wagner U, Kononen J et al (2001) Tissue microarray technology for high-throughput molecular profiling of cancer. Hum Mol Genet 10:657–662

    Article  PubMed  CAS  Google Scholar 

  31. Henriksen KL, Rasmussen BB, Lykkesfeldt AE et al (2007) Semi-quantitative scoring of potentially predictive markers for endocrine treatment of breast cancer: a comparison between whole sections and tissue microarrays. J Clin Pathol 60:397–404

    Article  PubMed  Google Scholar 

  32. Janssen EA, van Diest PJ, Søiland H et al (2006) Success predictors of adjuvant chemotherapy in node-negative breast cancer patients under 55 years. Cell Oncol 28:295–303

    PubMed  Google Scholar 

  33. Baker SG (2003) The central role of receiver operating characteristic (ROC) curves in evaluating tests for the early detection of cancer. J Natl Cancer Inst 95:511–515

    Article  PubMed  Google Scholar 

  34. Zlobec I, Steele R, Terracciano L et al (2007) Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol 60:1112–1116

    Article  PubMed  Google Scholar 

  35. Zweig MH, Campbell G (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39:561–577

    PubMed  CAS  Google Scholar 

  36. Altman DG, Lausen B, Sauerbrei W et al (1994) Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:829–835

    Article  PubMed  CAS  Google Scholar 

  37. Hermann RE, Steiger E (1978) Modified radical mastectomy. Surg Clin North Am 58:743–754

    PubMed  CAS  Google Scholar 

  38. The Norwegian Cancer Society, The Norwegian Surgical Society, The Norwegian Society of Therapeutic Oncology (1981) Primary treatment of breast cancer (National guidelines) (in Norwegian)

  39. Gundersen S, Hannisdal E, Søreide JA et al (1995) Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive, node positive breast cancer: a randomized study. Breast Cancer Res Treat 36:49–53

    Article  PubMed  CAS  Google Scholar 

  40. Organization web site: Norwegian Breast Cancer Group, http://www.nbcg.net. Cited 5 Jan 2008

  41. Lamelas ML, Vazquez J, Enguita MI et al (2000) Apolipoprotein D expression in metastasic lymph nodes of breast cancer. Int J Surg Investig 2:285–293

    PubMed  CAS  Google Scholar 

  42. Carreno G, Del Casar JM, Corte MD et al (2007) Local recurrence after mastectomy for breast cancer: analysis of clinicopathological, biological and prognostic characteristics. Breast Cancer Res Treat 102:61–73

    Article  PubMed  Google Scholar 

  43. Torhorst J, Bucher C, Kononen J et al (2001) Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol 159:2249–2256

    PubMed  CAS  Google Scholar 

  44. Polkowski W, Meijer GA, Baak JP et al (1997) Reproducibility of p53 and Ki-67 immunoquantitation in Barrett's esophagus. Anal Quant Cytol Histol 19:246–254

    PubMed  CAS  Google Scholar 

  45. Gennari R, Curigliano G, Rotmensz N et al (2004) Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopausal patients. Cancer 101:1302–1310

    Article  PubMed  Google Scholar 

  46. Muss HB, Biganzoli L, Sargent DJ et al (2007) Adjuvant therapy in the elderly: making the right decision. J Clin Oncol 25:1870–1875

    Article  PubMed  Google Scholar 

  47. Aspinall JO, Bentel JM, Horsfall DJ et al (1995) Differential expression of apolipoprotein-D and prostate specific antigen in benign and malignant prostate tissues. J Urol 154:622–628

    Article  PubMed  CAS  Google Scholar 

  48. Bianchi-Frias D, Pritchard C, Mecham BH et al (2007) Genetic background influences murine prostate gene expression: implications for cancer phenotypes. Genome Biol 8:R117

    Article  PubMed  CAS  Google Scholar 

  49. Hall RE, Horsfall DJ, Stahl J et al (2004) Apolipoprotein-D: a novel cellular marker for HGPIN and prostate cancer. Prostate 58:103–108

    Article  PubMed  CAS  Google Scholar 

  50. Miranda E, Vizoso F, Martin A et al (2003) Apolipoprotein D expression in cutaneous malignant melanoma. J Surg Oncol 83:99–105

    Article  PubMed  CAS  Google Scholar 

  51. Sanchez D, Lopez-Arias B, Torroja L et al (2006) Loss of glial lazarillo, a homolog of apolipoprotein D, reduces lifespan and stress resistance in Drosophila. Curr Biol 16:680–686

    Article  PubMed  CAS  Google Scholar 

  52. Walker DW, Muffat J, Rundel C et al (2006) Overexpression of a Drosophila homolog of apolipoprotein D leads to increased stress resistance and extended lifespan. Curr Biol 16:674–679

    Article  PubMed  CAS  Google Scholar 

  53. Janssen EA, Baak JP, Guervos MA et al (2003) In lymph node-negative invasive breast carcinomas, specific chromosomal aberrations are strongly associated with high mitotic activity and predict outcome more accurately than grade, tumour diameter, and oestrogen receptor. J Pathol 201:555–561

    Article  PubMed  CAS  Google Scholar 

  54. Skerra A (2007) Anticalins as alternative binding proteins for therapeutic use. Curr Opin Mol Ther 9:336–344

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Dr. Håvard Søiland, MD, is a Research Fellow, financially sponsored by the Western Norwegian Health Authorities (project # 911166). Financial support from The Norwegian Cancer Society, The L. Meltzer Foundation, and O. Mjålands Foundation is highly appreciated. We are grateful for the technical assistance of Britt Fjæran.

Author information

Authors and Affiliations

  1. Department of Surgery, Stavanger University Hospital, 4068, Stavanger, Norway

    Håvard Søiland, Hartwig Kørner & Jon Arne Søreide

  2. Department of Surgical Sciences, University of Bergen, Bergen, Norway

    Håvard Søiland, Hartwig Kørner, Jan Erik Varhaug & Jon Arne Søreide

  3. Department of Pathology, Stavanger University Hospital, Stavanger, Norway

    Emiel A. M. Janssen, Ivar Skaland, Einar Gudlaugsson & Jan P. A. Baak

  4. Section for Endocrine and Breast Surgery, Haukeland University Hospital, Bergen, Norway

    Jan Erik Varhaug

  5. The Gade Institute, University of Bergen, Bergen, Norway

    Jan P. A. Baak

  6. Free University, Amsterdam, The Netherlands

    Jan P. A. Baak

Authors
  1. Håvard Søiland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emiel A. M. Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hartwig Kørner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Erik Varhaug
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ivar Skaland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Einar Gudlaugsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jan P. A. Baak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jon Arne Søreide
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon Arne Søreide.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Søiland, H., Janssen, E.A.M., Kørner, H. et al. Apolipoprotein D predicts adverse outcome in women ≥70 years with operable breast cancer. Breast Cancer Res Treat 113, 519–528 (2009). https://doi.org/10.1007/s10549-008-9955-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-008-9955-y

Keywords

Search

Navigation