Skip to main content

Advertisement

Log in

Angiogenesis in triple-negative adenoid cystic carcinomas of the breast

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

We compared microvascular density (MVD), lymph vessel density (LVD), and the expression of hypoxia pathway-associated proteins between primary triple-negative adenoid cystic carcinoma of the breast (TN-ACC) and grade-matched triple-negative breast carcinomas of no special type (TNBC). Twelve TN-ACC and 15 TNBC were investigated immunohistochemically for CD31, podoplanin (D2-40), von Hippel–Lindau protein (pVHL), and hypoxia-inducible factor-1alpha (HIF-1α) protein. All cases were lymph node negative (pN0). The study revealed a median MVD (CD31) of 34 vessels/mm2 (mean ± SD, 41.33 ± 6.5/mm2) in the TN-ACC subgroup and a median of 55 microvessels (mean ± SD, 54.9 ± 6.3/mm2) in the TNBC subgroup. The median LVD (D2-40) was 10.5/mm2 (mean ± SD, 11.9 ± 1.5/mm2) in the TN-ACC subgroup and 15.0/mm2 (mean ± SD, 16.9 ± 2.5/mm2) lymph vessels in the TNBC subgroup. The differences were not statistically significant (P = 0.93, P = 0.67, respectively). pVHL was detectable in all TN-ACCs whereas two cases of TNBC had less than 5% of the positive cells. HIF-1α protein expression was significantly higher in the tumor cell population than in adjacent normal cells in both subgroups (P = 0.009 for TNBC and P = 0.028 for TN-ACC, respectively), but there was no significant difference between the two tumor groups. Up-regulation of the hypoxia-induced signaling is seen in both TN-ACC and grade-matched TNBC. Despite its perceived low malignant potential, TN-ACC of the breast does not differ in the number of blood and lymphatic vessels in comparison with the grade-matched TNBC. The reported biologic differences between TN-ACC and TNBC do not appear to result from neoangiogenesis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  3. Folkman J (2007) Is angiogenesis an organizing principle in biology and medicine? J Pediatr Surg 42:1–11

    Article  PubMed  Google Scholar 

  4. Weinberg RA (2007) The biology of cancer. Garland Science, Taylor & Francis Group, LLC, New York

    Google Scholar 

  5. Weidner N (2004) The importance of tumor angiogenesis. Am J Clin Pathol 122:675–677

    Article  PubMed  Google Scholar 

  6. Lundgren K, Holm C, Landberg G (2007) Hypoxia and breast cancer: prognostic and therapeutic implications. Cell Mol Life Sci 64:3233–3247

    Article  PubMed  CAS  Google Scholar 

  7. Haase VH (2006) The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int 69:1302–1307

    PubMed  CAS  Google Scholar 

  8. Calzada MJ (2010) Von Hippel-Lindau syndrome: molecular mechanisms of the disease. Clin Transl Oncol 12:160–165

    Article  PubMed  CAS  Google Scholar 

  9. Lantzsch T, Hefler L, Koelbl H, Lampe D (2002) Expression of von Hippel-Lindau gene protein in breast cancer tissue. Gynecol Oncol 84:186–187

    Article  PubMed  Google Scholar 

  10. Sourvinos G, Miyakis S, Liloglou TL, Field JK, Spandidos DA (2001) Von Hippel-Lindau tumour suppressor gene is not involved in sporadic human breast cancer. Tumour Biol 22:131–136

    Article  PubMed  CAS  Google Scholar 

  11. Corless CL, Kibel AS, Iliopoulos O, Kaelin WG Jr (1997) Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol 28:459–464

    Article  PubMed  CAS  Google Scholar 

  12. Mohammed RA, Ellis IO, Mahmmod AM et al (2011) Lymphatic and blood vessels in basal and triple-negative breast cancers: characteristics and prognostic significance. Mod Pathol 24:774–785

    Article  PubMed  CAS  Google Scholar 

  13. Sabatier R, Jacquemier J, Bertucci F et al (2011) Peritumoural vascular invasion: a major determinant of triple-negative breast cancer outcome. Eur J Cancer Mar 8 doi:10.1016/j.ejca.2011.02.002

  14. Khanfir K, Kallel A, Villette S et al (2011) Management of adenoid cystic carcinoma of the breast: a rare cancer network study. Int J Radiat Oncol Biol Phys (in press) May 11. doi:10.1016/j.ijrobp.2010.12.008

  15. Ghabach B, Anderson WF, Curtis RE, Huycke MM, Lavigne JA, Dores GM (2010) Adenoid cystic carcinoma of the breast in the United States (1977 to 2006): a population-based cohort study. Breast Cancer Res 12:R54

    Article  PubMed  Google Scholar 

  16. Vranic S, Frkovic-Grazio S, Lamovec J et al (2010) Adenoid cystic carcinomas of the breast have low Topo IIα expression but frequently overexpress EGFR protein without EGFR gene amplification. Hum Pathol 41:1617–1623

    Article  PubMed  CAS  Google Scholar 

  17. Edge SB, Byrd DR (2010) AJCC cancer staging manual, 7th edn. Springer, Berlin

    Google Scholar 

  18. Zhang XT, Kang LG, Ding L, Vranic S, Gatalica Z, Wang ZY (2011) A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene 30:770–780

    Article  PubMed  CAS  Google Scholar 

  19. Vranic S, Gurjeva O, Frkovic-Grazio S, Palazzo J, Tawfik O, Gatalica Z (2011) IMP3, a proposed novel basal phenotype marker, is commonly overexpressed in adenoid cystic carcinomas but not in apocrine carcinomas of the breast. Appl Immunohistochem Mol Morphol Mar 22 (in press) doi:10.1097/PAI.0b013e3182143399

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

    Article  PubMed  CAS  Google Scholar 

  21. Yan M, Rayoo M, Takano EA, KConFab Investigators, Fox SB (2009) BRCA1 tumours correlate with a HIF-1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression. Br J Cancer 101:1168–1174

    Article  PubMed  CAS  Google Scholar 

  22. Vranic S, Bilalovic N, Lee LM, Kruslin B, Lilleberg SL, Gatalica Z (2007) PIK3CA and PTEN mutations in adenoid cystic carcinoma of the breast metastatic to kidney. Hum Pathol 38:1425–1431

    Article  PubMed  CAS  Google Scholar 

  23. Weigelt B, Geyer FC, Reis-Filho JS (2010) Histological types of breast cancer: How special are they? Mol Oncol 4:192–208

    Article  PubMed  CAS  Google Scholar 

  24. Weigelt B, Horlings HM, Kreike B et al (2008) Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 216:141–150

    Article  PubMed  CAS  Google Scholar 

  25. Otrock ZK, Hatoum HA, Awada AH et al (2009) Hypoxia-inducible factor in cancer angiogenesis: structure, regulation and clinical perspectives. Crit Rev Oncol Hemat 70:93–102

    Article  Google Scholar 

  26. Voss MJ, Moller MF, Powe DG, Niggemann B, Zanker KS, Entschladen F (2011) Luminal and basal-like breast cancer cell show increased migration induced by hypoxia, mediated by an autocrine mechanism. BMC Cancer 11:158

    Article  PubMed  CAS  Google Scholar 

  27. Bos R, Zhong H, Hanrahan CF et al (2001) Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 93:309–314

    Article  PubMed  CAS  Google Scholar 

  28. Kimbro KS, Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13:739–749

    Article  PubMed  CAS  Google Scholar 

  29. Carroll V, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1A versus HIF-2A in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66:6264–6270

    Article  PubMed  CAS  Google Scholar 

  30. Bos R, van Diest PJ, de Jong JS, van der Groep P, van der Valk P, van der Wall E (2005) Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 46:31–36

    Article  PubMed  CAS  Google Scholar 

  31. Bos R, van der GP, Greijer AE et al (2003) Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97:1573–1581

    Article  PubMed  Google Scholar 

  32. Ryu K, Park C, Lee Y (2011) Hypoxia-inducible factor 1 alpha represses the transcription of the estrogen receptor alpha gene in human breast cancer cells. Biochem Biophys Res Commun 407:831–836

    Article  PubMed  CAS  Google Scholar 

  33. Rakha EA, Elsheikh SE, Aleskandarany MA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15:2302–2310

    Article  PubMed  CAS  Google Scholar 

  34. Vleugel MM, Bos R, Buerger H et al (2004) No amplifications of hypoxia-inducible factor-1alpha gene in invasive breast cancer: a tissue microarray study. Cell Oncol 26:347–351

    PubMed  CAS  Google Scholar 

  35. Trastour C, Benizri E, Ettore F et al (2007) HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120:1451–1458

    Article  PubMed  CAS  Google Scholar 

  36. van der Groep P, Bouter A, Menko FH, van der Wall E, van Diest PJ (2008) High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer. Breast Cancer Res Treat 111:475–480

    Article  PubMed  CAS  Google Scholar 

  37. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  PubMed  CAS  Google Scholar 

  38. Lin F, Shi J, Liu H et al (2008) Immunohistochemical detection of the von Hippel-Lindau gene product (pVHL) in human tissues and tumors: a useful marker for metastatic renal cell carcinoma and clear cell carcinoma of the ovary and uterus. Am J Clin Pathol 129:592–605

    Article  PubMed  CAS  Google Scholar 

  39. Lopez-Garcia MA, Wetterskog D, Lambros MB et al (2011) Genomic profiling of adenoid cystic carcinomas of the breast. Mod Pathol 24(suppl1):52A (meeting abstract 205)

    Google Scholar 

Download references

Acknowledgments

We are grateful to Ms. Mindee C. Kurtis, Creighton Medical Laboratories, Creighton University Medical Center (Omaha, NE) for excellent technical assistance.

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Semir Vranic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vranic, S., Frkovic-Grazio, S., Bilalovic, N. et al. Angiogenesis in triple-negative adenoid cystic carcinomas of the breast. Virchows Arch 459, 377–382 (2011). https://doi.org/10.1007/s00428-011-1144-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-011-1144-4

Keywords

Navigation