Skip to main content

Advertisement

SpringerLink
Log in

Human achaete-scute homolog-1 expression in neuroendocrine breast carcinoma

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

Abstract

Neuroendocrine (NE) breast carcinoma is defined by morphological features similar to those of NE tumors of other organs and NE marker expression in at least 50 % of neoplastic cells. However, a NE morphology may be observed even in breast carcinomas lacking NE markers. Human achaete-scute homolog-1 (hASH-1) is a transcription factor that plays a key role in the regulation of mammalian neural and NE cell development and has been identified in several human NE tumors. The aim of this study was to investigate hASH-1 expression in human breast cancers. hASH-1 expression was evaluated in 482 consecutive non-NE invasive breast carcinomas, in a series of 84 breast cancers with >50 % NE marker expression (high NE differentiation) and 21 carcinomas with NE histology but negative or focally (<50 %) positive for NE markers (low NE differentiation). hASH-1 protein was evaluated by a specific monoclonal antibody using immunohistochemistry and gene expression by real-time polymerase chain reaction. None of the non-NE invasive breast carcinomas expressed hASH-1 at any levels. hASH-1 was expressed in tumor cell nuclei of 63 and 38 % of cases with high and low NE differentiation, respectively. Strong correlation with protein and gene expression levels was observed (p < 0.0001). hASH-1 expression was correlated to a low mitotic count (p = 0.02) and a low Ki67 proliferative index (p = 0.0062). hASH-1 expression occurs in breast cancers with NE differentiation regardless of the extent of the NE cell population, and it is restricted to a subset of tumor cells having a low proliferative potential.

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
Fig. 5

Similar content being viewed by others

References

  1. Cubilla AL, Woodruff JM (1977) Primary carcinoid tumor of the breast. A report of eight patients. Am J Surg Pathol 1:283–292

    Article  Google Scholar 

  2. Ellis P, Schnitt SJ, Sastre-Garau X (2003) Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) Tumours of the breast and female genital organs. Pathology and genetics. World Health Organization Classification of Tumours. IARC Press, Lyon

    Google Scholar 

  3. Righi L, Sapino A, Marchio C, Papotti M, Bussolati G (2010) Neuroendocrine differentiation in breast cancer: established facts and unresolved problems. Semin Diagn Pathol 27(1):69–76

    Article  PubMed  Google Scholar 

  4. Wei B, Ding T, Xing Y, Wei W, Tian Z, Tang F, Abraham S, Nayeemuddin K, Hunt K, Wu Y (2010) Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer 116(19):4463–4473. doi:10.1002/cncr.25352

    Article  PubMed  Google Scholar 

  5. Tavassoli F, Eusebi V (2009) AFIP atlas of tumor pathology. Armed Forces Institute of Pathology, Washington DC

    Google Scholar 

  6. Lopez-Bonet E, Alonso-Ruano M, Barraza G, Vazquez-Martin A, Bernado L, Menendez JA (2008) Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 20(6):1369–1374

    PubMed  Google Scholar 

  7. Miremadi A, Pinder SE, Lee AH, Bell JA, Paish EC, Wencyk P, Elston CW, Nicholson RI, Blamey RW, Robertson JF, Ellis IO (2002) Neuroendocrine differentiation and prognosis in breast adenocarcinoma. Histopathology 40(3):215–222

    Article  PubMed  CAS  Google Scholar 

  8. Sapino A, Bussolati G (2002) Is detection of endocrine cells in breast adenocarcinoma of diagnostic and clinical significance? Histopathology 40(3):211–214

    Article  PubMed  CAS  Google Scholar 

  9. Sapino A, Righi L, Cassoni P, Papotti M, Pietribiasi F, Bussolati G (2000) Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol 17(2):127–137

    PubMed  CAS  Google Scholar 

  10. Moriya T, Kanomata N, Kozuka Y, Fukumoto M, Iwachido N, Hata S, Takahashi Y, Miura H, Ishida K, Watanabe M (2009) Usefulness of immunohistochemistry for differential diagnosis between benign and malignant breast lesions. Breast Cancer 16(3):173–178

    Article  PubMed  Google Scholar 

  11. Capella C, Usellini L, Papotti M, Macri L, Finzi G, Eusebi V, Bussolati G (1990) Ultrastructural features of neuroendocrine differentiated carcinomas of the breast. Ultrastruct Pathol 14(4):321–334

    Article  PubMed  CAS  Google Scholar 

  12. Massari ME, Murre C (2000) Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 20(2):429–440

    Article  PubMed  CAS  Google Scholar 

  13. Casarosa S, Fode C, Guillemot F (1999) Mash1 regulates neurogenesis in the ventral telencephalon. Development 126(3):525–534

    PubMed  CAS  Google Scholar 

  14. Guillemot F, Joyner AL (1993) Dynamic expression of the murine Achaete-Scute homologue Mash-1 in the developing nervous system. Mech Dev 42(3):171–185

    Article  PubMed  CAS  Google Scholar 

  15. Huber K, Bruhl B, Guillemot F, Olson EN, Ernsberger U, Unsicker K (2002) Development of chromaffin cells depends on MASH1 function. Development 129(20):4729–4738

    PubMed  CAS  Google Scholar 

  16. Tomita K, Nakanishi S, Guillemot F, Kageyama R (1996) Mash1 promotes neuronal differentiation in the retina. Genes Cells 1(8):765–774

    Article  PubMed  CAS  Google Scholar 

  17. Hirsch MR, Tiveron MC, Guillemot F, Brunet JF, Goridis C (1998) Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development 125(4):599–608

    PubMed  CAS  Google Scholar 

  18. Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW (1997) An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386(6627):852–855

    Article  PubMed  CAS  Google Scholar 

  19. Osada H, Tomida S, Yatabe Y, Tatematsu Y, Takeuchi T, Murakami H, Kondo Y, Sekido Y, Takahashi T (2008) Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res 68(6):1647–1655

    Article  PubMed  CAS  Google Scholar 

  20. Rostomily RC, Bermingham-McDonogh O, Berger MS, Tapscott SJ, Reh TA, Olson JM (1997) Expression of neurogenic basic helix-loop-helix genes in primitive neuroectodermal tumors. Cancer Res 57(16):3526–3531

    PubMed  CAS  Google Scholar 

  21. Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD (1993) Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci USA 90(12):5648–5652

    Article  PubMed  CAS  Google Scholar 

  22. Shida T, Furuya M, Nikaido T, Kishimoto T, Koda K, Oda K, Nakatani Y, Miyazaki M, Ishikura H (2005) Aberrant expression of human achaete-scute homologue gene 1 in the gastrointestinal neuroendocrine carcinomas. Clin Cancer Res 11(2 Pt 1):450–458

    PubMed  CAS  Google Scholar 

  23. Miki M, Ball DW, Linnoila RI (2011) Insights into the achaete-scute homolog-1 gene (hASH1) in normal and neoplastic human lung. Lung cancer (Amsterdam, Netherlands). doi:10.1016/j.lungcan.2011.05.019

  24. Rapa I, Ceppi P, Bollito E, Rosas R, Cappia S, Bacillo E, Porpiglia F, Berruti A, Papotti M, Volante M (2008) Human ASH1 expression in prostate cancer with neuroendocrine differentiation. Mod Pathol 21(6):700–707

    Article  PubMed  CAS  Google Scholar 

  25. Vias M, Massie CE, East P, Scott H, Warren A, Zhou Z, Nikitin AY, Neal DE, Mills IG (2008) Pro-neural transcription factors as cancer markers. BMC Med Genomics 1:17. doi:10.1186/1755-8794-1-17

    Article  PubMed  Google Scholar 

  26. Hartman J, Lam EW, Gustafsson JA, Strom A (2009) Hes-6, an inhibitor of Hes-1, is regulated by 17beta-estradiol and promotes breast cancer cell proliferation. Breast Cancer Res 11(6):R79. doi:10.1186/bcr2446

    Article  PubMed  Google Scholar 

  27. Capella C, Eusebi V, Mann B, Azzopardi JG (1980) Endocrine differentiation in mucoid carcinoma of the breast. Histopathology 4(6):613–630

    Article  PubMed  CAS  Google Scholar 

  28. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, Lo Iacono M, Cappia S, Papotti M, Scagliotti GV (2006) Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107(7):1589–1596

    Article  PubMed  CAS  Google Scholar 

  29. Heid CA, Stevens J, Livak KJ, Williams PM (1996) Real time quantitative PCR. Genome Res 6(10):986–994

    Article  PubMed  CAS  Google Scholar 

  30. Righi L, Papotti MG, Ceppi P, Bille A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV, Selvaggi G (2010) Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol 28(9):1534–1539. doi:10.1200/JCO.2009.25.9275

    Article  PubMed  CAS  Google Scholar 

  31. Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL (1993) Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell 75(3):463–476

    Article  PubMed  CAS  Google Scholar 

  32. Linnoila RI, Zhao B, DeMayo JL, Nelkin BD, Baylin SB, DeMayo FJ, Ball DW (2000) Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice. Cancer Res 60(15):4005–4009

    PubMed  CAS  Google Scholar 

  33. Iyoda A, Hiroshima K, Toyozaki T, Haga Y, Fujisawa T, Ohwada H (2001) Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 91(11):1992–2000

    Article  PubMed  CAS  Google Scholar 

  34. Sapino A, Righi L, Cassoni P, Papotti M, Gugliotta P, Bussolati G (2001) Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women. Mod Pathol 14(8):768–776

    Article  PubMed  CAS  Google Scholar 

  35. Ball DW (2004) Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Cancer Lett 204(2):159–169

    Article  PubMed  CAS  Google Scholar 

  36. Axelson H (2004) The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1. Cancer Lett 204(2):171–178. doi:10.1016/S0304-3835(03)00453-1

    Article  PubMed  CAS  Google Scholar 

  37. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors do not have any conflicts of interest to declare with regard to the current study.

Author information

Authors and Affiliations

  1. Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy

    Luisella Righi, Ida Rapa, Arianna Votta & Mauro Papotti

  2. Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy

    Anna Sapino

  3. Department of Clinical and Biological Sciences, Pathology Unit, University of Turin al San Luigi Hospital, Regione Gonzole 10, 10143, Orbassano, Turin, Italy

    Luisella Righi

Authors
  1. Luisella Righi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ida Rapa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arianna Votta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mauro Papotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Sapino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luisella Righi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Righi, L., Rapa, I., Votta, A. et al. Human achaete-scute homolog-1 expression in neuroendocrine breast carcinoma. Virchows Arch 460, 415–421 (2012). https://doi.org/10.1007/s00428-012-1223-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1223-1

Keywords

Search

Navigation