Skip to main content

Advertisement

SpringerLink
Log in

Vascular proliferation is increased in basal-like breast cancer

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Based on molecular sub-classification, basal-like breast cancer is associated with aggressive behavior. These tumors are frequently triple negative and lack traditional treatment targets. Angiogenesis, one of the hallmarks of cancer, is important for the local growth and spread of malignant tumors and is now a treatment target. The aim of this study was to explore whether angiogenesis is increased in relation to certain molecular subtypes of breast cancer with special focus on the basal-like category. Altogether, we analyzed a total of 431 breast cancers from two independent series after dual immunohistochemical staining of Factor VIII for endothelial cells and Ki-67 for proliferating cells. We then determined vascular proliferation in the most vascularized areas of the tumor. In both Series I and II, high vascular proliferation index (VPI) was significantly associated with expression of cytokeratin 5/6 (P = 0.001, 0.010), P-cadherin (P < 0.0005, <0.0005), epidermal growth factor receptor (P = 0.003, 0.001), the basal-like subtype (P = 0.001, 0.011), and the core basal phenotype (P = 0.002, 0.002), respectively. In Series I, high VPI was associated with the triple negative phenotype (P = 0.004) and p63 expression (P = 0.008). Tumor angiogenesis, as measured by vascular proliferation, was increased in the basal-like subtype in two independent breast cancer series and may thus be a possible treatment target in this category. Studies are required to evaluate whether this novel angiogenesis marker can be used to stratify patients for anti-angiogenesis treatment.

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

References

  1. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.191367098

    Article  PubMed  CAS  Google Scholar 

  2. Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26(15):2568–2581. doi:10.1200/JCO.2007.13.1748

    Article  PubMed  Google Scholar 

  3. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7:134. doi:10.1186/1471-2407-7-134

    Article  PubMed  Google Scholar 

  4. Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT, Tubbs RR, Casey G, Weil RJ (2006) Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 30(9):1097–1104. doi:10.1097/01.pas.0000213306.05811.b9

    PubMed  Google Scholar 

  5. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1):4–6. doi:10.1093/jnci/82.1.4

    Article  PubMed  CAS  Google Scholar 

  6. Fox SB, Generali DG, Harris AL (2007) Breast tumour angiogenesis. Breast Cancer Res 9(6):216. doi:10.1186/bcr1796

    Article  PubMed  Google Scholar 

  7. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70. doi:10.1016/S0092-8674(00)81683-9

    Article  PubMed  CAS  Google Scholar 

  8. Lopes N, Sousa B, Vieira D, Milanezi F, Schmitt F (2009) Vessel density assessed by endoglin expression in breast carcinomas with different expression profiles. Histopathology 55(5):594–599. doi:10.1111/j.1365-2559.2009.03417.x

    Article  PubMed  Google Scholar 

  9. Ribeiro-Silva A, Ribeiro do Vale F, Zucoloto S (2006) Vascular endothelial growth factor expression in the basal subtype of breast carcinoma. Am J Clin Pathol 125(4):512–518. doi:10.1309/D744C4NM15J3B00D

    PubMed  CAS  Google Scholar 

  10. Goffin JR, Straume O, Chappuis PO, Brunet JS, Begin LR, Hamel N, Wong N, Akslen LA, Foulkes WD (2003) Glomeruloid microvascular proliferation is associated with p53 expression, germline BRCA1 mutations and an adverse outcome following breast cancer. Br J Cancer 89(6):1031–1034. doi:10.1038/sj.bjc.6601195

    Article  PubMed  CAS  Google Scholar 

  11. Straume O, Chappuis PO, Salvesen HB, Halvorsen OJ, Haukaas SA, Goffin JR, Begin LR, Foulkes WD, Akslen LA (2002) Prognostic importance of glomeruloid microvascular proliferation indicates an aggressive angiogenic phenotype in human cancers. Cancer Res 62(23):6808–6811

    PubMed  CAS  Google Scholar 

  12. Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Begin LR, Hamel N, Goffin JR, Wong N, Trudel M, Kapusta L, Porter P, Akslen LA (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64(3):830–835. doi:10.1158/0008-5472.CAN-03-2970

    Article  PubMed  CAS  Google Scholar 

  13. Hlatky L, Hahnfeldt P, Folkman J (2002) Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn’t tell us. J Natl Cancer Inst 94(12):883–893. doi:10.1093/jnci/94.12.883

    Article  PubMed  Google Scholar 

  14. Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA (2009) Proliferation of immature tumor vessels is a novel marker of clinical progression in prostate cancer. Cancer Res 69(11):4708–4715. doi:10.1158/0008-5472.CAN-08-4417

    Article  PubMed  CAS  Google Scholar 

  15. Stefansson IM, Salvesen HB, Akslen LA (2006) Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res 66(6):3303–3309. doi:10.1158/0008-5472.CAN-05-1163

    Article  PubMed  CAS  Google Scholar 

  16. Nalwoga H, Arnes JB, Wabinga H, Akslen LA (2010) Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer. Br J Cancer 102(2):369–375. doi:10.1038/sj.bjc.6605488

    Article  PubMed  CAS  Google Scholar 

  17. Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, Trudel M, Akslen LA (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95(19):1482–1485. doi:10.1093/jnci/djg050

    Article  PubMed  CAS  Google Scholar 

  18. Arnes JB, Begin LR, Stefansson I, Brunet JS, Nielsen TO, Foulkes WD, Akslen LA (2009) Expression of epidermal growth factor receptor in relation to BRCA1 status, basal-like markers and prognosis in breast cancer. J Clin Pathol 62(2):139–146. doi:10.1136/jcp.2008.056291

    Article  PubMed  CAS  Google Scholar 

  19. Nalwoga H, Arnes JB, Wabinga H, Akslen LA (2008) Expression of EGFR and c-kit is associated with the basal-like phenotype in breast carcinomas of African women. APMIS 116(6):515–525. doi:10.1111/j.1600-0463.2008.01024.x

    Article  PubMed  CAS  Google Scholar 

  20. Engelsen IB, Stefansson I, Akslen LA, Salvesen HB (2006) Pathologic expression of p53 or p16 in preoperative curettage specimens identifies high-risk endometrial carcinomas. Am J Obstet Gynecol 195(4):979–986. doi:10.1016/j.ajog.2006.02.045

    Article  PubMed  CAS  Google Scholar 

  21. Stefansson IM, Salvesen HB, Akslen LA (2006) Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients. Int J Cancer 118(5):1227–1233. doi:10.1002/ijc.21415

    Article  PubMed  CAS  Google Scholar 

  22. Arnes JB, Brunet JS, Stefansson I, Begin LR, Wong N, Chappuis PO, Akslen LA, Foulkes WD (2005) Placental cadherin and the basal epithelial phenotype of BRCA1-related breast cancer. Clin Cancer Res 11(11):4003–4011. doi:10.1158/1078-0432.CCR-04-2064

    Article  PubMed  CAS  Google Scholar 

  23. Yuan ZQ, Begin LR, Wong N, Brunet JS, Trifiro M, Gordon PH, Pinsky L, Foulkes WD (1999) The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer. Br J Cancer 81(5):850–854. doi:10.1038/sj.bjc.6690775

    Article  PubMed  CAS  Google Scholar 

  24. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  PubMed  CAS  Google Scholar 

  25. Sihto H, Lundin J, Lehtimaki T, Sarlomo-Rikala M, Butzow R, Holli K, Sailas L, Kataja V, Lundin M, Turpeenniemi-Hujanen T, Isola J, Heikkila P, Joensuu H (2008) Molecular subtypes of breast cancers detected in mammography screening and outside of screening. Clin Cancer Res 14(13):4103–4110. doi:10.1158/1078-0432.CCR-07-5003

    Article  PubMed  CAS  Google Scholar 

  26. Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B et al (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16(3):439–443. doi:10.1158/1055-9965.EPI-06-0806

    Article  PubMed  CAS  Google Scholar 

  27. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn MV, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.CCR-04-0220

    Article  PubMed  CAS  Google Scholar 

  28. Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med 324(1):1–8

    Article  PubMed  CAS  Google Scholar 

  29. Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Borresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, van de Vijver MJ, Brown PO (2006) Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 3(3):e47. doi:10.1371/journal.pmed.0030047

    Article  PubMed  Google Scholar 

  30. Dent SF (2009) The role of VEGF in triple-negative breast cancer: where do we go from here? Ann Oncol 20(10):1615–1617. doi:10.1093/annonc/mdp410

    Article  PubMed  CAS  Google Scholar 

  31. Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Perou CM (2009) A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med 7:9. doi:10.1186/1741-7015-7-9

    Article  PubMed  Google Scholar 

  32. Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtio J, Lewensohn R (2009) Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol 20(10):1639–1646. doi:10.1093/annonc/mdp062

    Article  PubMed  CAS  Google Scholar 

  33. Nieto Y, Woods J, Nawaz F, Baron A, Jones RB, Shpall EJ, Nawaz S (2007) Prognostic analysis of tumour angiogenesis, determined by microvessel density and expression of vascular endothelial growth factor, in high-risk primary breast cancer patients treated with high-dose chemotherapy. Br J Cancer 97(3):391–397. doi:10.1038/sj.bjc.6603875

    Article  PubMed  CAS  Google Scholar 

  34. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. doi:10.1158/0008-5472.CAN-04-1443

    Article  PubMed  CAS  Google Scholar 

  35. Hoadley KA, Weigman VJ, Fan C, Sawyer LR, He X, Troester MA, Sartor CI, Rieger-House T, Bernard PS, Carey LA, Perou CM (2007) EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 8:258. doi:10.1186/1471-2164-8-258

    Article  PubMed  Google Scholar 

  36. Senoo M, Matsumura Y, Habu S (2002) TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene 21(16):2455–2465. doi:10.1038/sj.onc.1205330

    Article  PubMed  CAS  Google Scholar 

  37. Barbareschi M, Pecciarini L, Cangi MG, Macri E, Rizzo A, Viale G, Doglioni C (2001) p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. Am J Surg Pathol 25(8):1054–1060

    Article  PubMed  CAS  Google Scholar 

  38. Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW (2007) The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Investig 117(5):1370–1380. doi:10.1172/JCI30866

    Article  PubMed  CAS  Google Scholar 

  39. 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):688–694. doi:10.1007/s00428-005-0010-7

    Article  PubMed  CAS  Google Scholar 

  40. Fourati A, Khomsi F, El May MV, Rahal K, Gamoudi A, Boussen H, Ben Abdallah M, El May A (2007) Correlation between P53 expression and CD34 angiogenic factor in Tunisian breast cancer. Tunis Med 85(2):105–108

    PubMed  Google Scholar 

  41. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14(1):34–44. doi:10.1101/gad.14.1.34

    PubMed  CAS  Google Scholar 

  42. Volpert OV, Stellmach V, Bouck N (1995) The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. Breast Cancer Res Treat 36(2):119–126. doi:10.1007/BF00666034

    Article  PubMed  CAS  Google Scholar 

  43. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21(12):3995–4004. doi:10.1128/MCB.21.12.3995-4004.2001

    Article  PubMed  CAS  Google Scholar 

  44. Koukourakis MI, Manolas C, Minopoulos G, Giatromanolaki A, Sivridis E (2003) Angiogenesis relates to estrogen receptor negativity, c-erbB-2 overexpression and early relapse in node-negative ductal carcinoma of the breast. Int J Surg Pathol 11(1):29–34. doi:10.1177/106689690301100107

    Article  PubMed  CAS  Google Scholar 

  45. Vamesu S (2007) Angiogenesis and c-erbB-2 (HER2/neu) overexpression status in primary breast cancer patients: an analysis of 158 needle core biopsies. Rom J Morphol Embryol 48(2):121–129. doi:480207121129[pii]

    PubMed  CAS  Google Scholar 

  46. Kato T, Kameoka S, Kimura T, Nishikawa T, Kasajima T (2001) Angiogenesis and blood vessel invasion as prognostic indicators for node-negative breast cancer. Breast Cancer Res Treat 65(3):203–215. doi:10.1023/A:1010668616265

    Article  PubMed  CAS  Google Scholar 

  47. Morabito A, Sarmiento R, Bonginelli P, Gasparini G (2004) Antiangiogenic strategies, compounds, and early clinical results in breast cancer. Crit Rev Oncol Hematol 49(2):91–107. doi:10.1016/S1040-8428(03)00168-9

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the University of Bergen and Makerere University for establishing the collaboration through which this study was funded. We thank the Department of Pathology at MUCHS for allowing us to use the archival tissue and the Kampala Cancer Registry for providing us with supporting data. We thank the Centre for Disease Control and Prevention (USA) for the computerized data base at Department of Pathology MUCHS. We are also grateful for the excellent technical help offered by Ms. Gerd Lillian Hallseth, Ms. Dorothy Lynn Nabbale, Ms. Ruth Nakigudde, Mr. Bendik Nordanger, and Ms Randi Nygaard. We acknowledge the Norwegian Government, The Norwegian Cancer Society, The Norwegian Research Council, Helse Vest RHF, and Susan G. Komen for the Cure for funding this study.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, 5021, Bergen, Norway

    Hawa Nalwoga, Jarle B. Arnes, Ingunn M. Stefansson & Lars A. Akslen

  2. Department of Pathology, Makerere University College of Health Sciences, P. O. Box 7072, Kampala, Uganda

    Hawa Nalwoga & Henry Wabinga

  3. Department of Pathology, Haukeland University Hospital, 5021, Bergen, Norway

    Ingunn M. Stefansson & Lars A. Akslen

  4. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, 546 Pine Avenue West, Montreal, QC, H2W 1S6, Canada

    William D. Foulkes

Authors
  1. Hawa Nalwoga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jarle B. Arnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ingunn M. Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Henry Wabinga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars A. Akslen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars A. Akslen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nalwoga, H., Arnes, J.B., Stefansson, I.M. et al. Vascular proliferation is increased in basal-like breast cancer. Breast Cancer Res Treat 130, 1063–1071 (2011). https://doi.org/10.1007/s10549-011-1740-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1740-7

Keywords

Search

Navigation