Skip to main content

Advertisement

Log in

The role of tumor hypoxia in MUC1-positive breast carcinomas

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

Abstract

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell–cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1α) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1α and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1α (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-κB (IκBα), driving NF-κB to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-κB expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-κB to the nucleus. Our data also support the notion that activation of HIF-1α in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Ribeiro-Silva A, Moutinho MA, Moura HB et al (2006) Expression of checkpoint kinase 2 in breast carcinomas: correlation with key regulators of tumor cell proliferation, angiogenesis, and survival. Histol Histopathol 21:373–382

    PubMed  CAS  Google Scholar 

  2. Koda M, Kanczuga-Koda L, Sulkowska M et al (2010) Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy. BMC Cancer 10:1–8

    Article  Google Scholar 

  3. Sun L, Lin S, Zhao R et al (2010) The saponin monomer of dwarf lilyturf tuber, DT-13, reduces human breast cancer cell adhesion and migration during hypoxia via regulation of tissue factor. Biol Pharm Bull 33:1192–1198

    Article  PubMed  CAS  Google Scholar 

  4. Vordermark D (2010) Hypoxia-specific targets in cancer therapy: role of splice variants. BMC Med 12:1–3

    Google Scholar 

  5. Chen CL, Chu JS, Su WC (2010) Hypoxia and metabolic phenotypes during breast carcinogenesis: expression of HIF-1α, GLUT1, and CAIX. Virchows Arch 457:53–61

    Article  PubMed  CAS  Google Scholar 

  6. Giatromanolaki A, Koukourakis MI, Sivridis E et al (2001) Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 61:7992–7998

    PubMed  CAS  Google Scholar 

  7. Schumacher U, Adam E (1998) Immunohistochemical detection of the MUC1 gene product in human cancers grown in scid mice. J Histochem Cytochem 46:127–134

    Article  PubMed  CAS  Google Scholar 

  8. Rakha EA, Boyce WG, El-Rehim DA et al (2005) Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol 18:1295–1304

    Article  PubMed  CAS  Google Scholar 

  9. O'Connell JT, Zhi-Ming S, Ehud D et al (1998) Altered mucin expression is a field change that accompanies mucinous (colloid) breast carcinoma histogenesis. Hum Pathol 29:1517–1523

    Article  PubMed  Google Scholar 

  10. Raina D, Ahmad R, Joshi MD et al (2009) Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res 69:5133–5141

    Article  PubMed  CAS  Google Scholar 

  11. Voynow JA, Gendler SJ, Rose MC (2006) Regulation of mucin genes in chronic inflammatory airway diseases. Am J Respir Cell Mol Biol 34:661–665

    Article  PubMed  CAS  Google Scholar 

  12. Nassar H, Pansare V, Zhang H et al (2004) Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol 17:1045–1050

    Article  PubMed  CAS  Google Scholar 

  13. Abba MC, Nunez MI, Colussi AG et al (2006) GATA3 protein as a MUC1 transcriptional regulator in breast cancer cells. Breast Cancer Res 8:R64

    Article  PubMed  Google Scholar 

  14. Heuser C, Ganser M, Hombach A et al (2003) An anti-MUC1-antibody–interleukin-2 fusion protein that activates resting NK cells to lysis of MUC1-positive tumour cells. Br J Cancer 89:1130–1139

    Article  PubMed  CAS  Google Scholar 

  15. Hattrup CL, Gendler SJ (2006) MUC1 alters oncogenic events and transcription in human breast cancer cells. Breast Cancer Res 8:R37

    Article  PubMed  Google Scholar 

  16. Khodarev NN, Pitroda SP, Beckett MA et al (2009) MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. Cancer Res 69:2833–2837

    Article  PubMed  CAS  Google Scholar 

  17. Brayman MJ, Dharmaraj N, Lagow E et al (2007) MUC1 expression is repressed by protein inhibitor of activated signal transducer and activator of transcription-y. Mol Endocrinol 21:2725–2737

    Article  PubMed  CAS  Google Scholar 

  18. Huyn ST, Burton JB, Sato M et al (2009) A potent, imaging adenoviral vector driven by the cancer-selective mucin-1 promoter that targets breast cancer metastasis. Clin Cancer Res 15:3126–3134

    Article  PubMed  CAS  Google Scholar 

  19. Yin L, Li Y, Ren J et al (2003) Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J Biol Chem 278:35458–3564

    Article  PubMed  CAS  Google Scholar 

  20. Apostolopoulos V, Mckenzie IF, Pietersz GA (1996) Breast cancer immunotherapy: current status and future prospects. Immunol Cell Biol 74:457–464

    Article  PubMed  CAS  Google Scholar 

  21. Fitzgibbons PL, Page DL, Weaver D et al (2000) Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124:966–978

    PubMed  CAS  Google Scholar 

  22. Mangia A, Chiriatti A, Tommasi S et al (2009) BRCA1 expression and molecular alterations in familial breast cancer. Histol Histopathol 24:69–76

    PubMed  CAS  Google Scholar 

  23. Rydén L, Jirstro K, Haglund M et al (2010) Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up. Breast Cancer Res Treat 120:491–498

    Article  PubMed  Google Scholar 

  24. Sangoi AR, Higgins JP, Rouse RV et al (2009) Immunohistochemical comparison of MUC1, CA125, and Her2Neu in invasive micropapillary carcinoma of the urinary tract and typical invasive urothelial carcinoma with retraction artifact. Mod Pathol 22:660–667

    Article  PubMed  CAS  Google Scholar 

  25. Singletary SE, Greene FL (2003) Revision of breast cancer staging: the 6th edition of the TNM classification. Semin Surg Oncol 21:53–59

    Article  PubMed  Google Scholar 

  26. Lagow EL, Carson DD (2002) Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-γ and tumor necrosis factor-α. J Cell Biochem 86:759–772

    Article  PubMed  CAS  Google Scholar 

  27. Ahmad R, Raina D, Trivedi V et al (2007) MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling. Nat Cell Biol 9:1419–1427

    Article  PubMed  CAS  Google Scholar 

  28. Zhou X, DeSouza MM, Julian J et al (1998) Estrogen receptor does not directly regulate the murine Muc-1 promoter. Mol Cell Endocrinol 143:65–78

    Article  PubMed  CAS  Google Scholar 

  29. Braz MM, Ramalho FS, Cardoso RL et al (2010) Slight activation of nuclear factor kappa-B is associated with increased hepatic stellate cell apoptosis in human schistosomal fibrosis. Acta Trop 113:66–71

    Article  PubMed  CAS  Google Scholar 

  30. Nakshatri H, Nakshatri PB, Martin DA et al (1997) Constitutive activation of NF-kB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639

    PubMed  CAS  Google Scholar 

  31. Chang F, Lee JT, Navolanic PM et al (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17:590–603

    Article  PubMed  CAS  Google Scholar 

  32. Oliveira-Costa JP, Zanetti J, Oliveira LR et al (2010) Significance of topoisomerase IIIβ expression in breast ductal carcinomas: strong associations with disease-specific survival and metastasis. Hum Pathol 41:1624–1630

    Article  PubMed  CAS  Google Scholar 

  33. Urruticoechea A, Smith IE, Dowsett M (2005) Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212–7220

    Article  PubMed  CAS  Google Scholar 

  34. Ban HS, Uno M, Nakamura H (2010) Suppression of hypoxia-induced HIF-1a accumulation by VEGFR inhibitors: different profiles of AAL993 versus SU5416 and KRN633. Cancer Lett 296:17–26

    Article  PubMed  CAS  Google Scholar 

  35. Qiao Q, Nozaki Y, Sakoe K et al (2010) NF-kB mediates aberrant activation of HIF-1 in malignant lymphoma. Exp Hemathol 38:1199–1208

    Article  CAS  Google Scholar 

  36. Sharma V, Dixit D, Koul N et al (2011) Ras regulates interleukin-1β-induced HIF-1α transcriptional activity in glioblastoma. J Mol Med 89:123–136

    Article  PubMed  CAS  Google Scholar 

  37. Newton IP, Kenneth NS, Appleton PL et al (2010) Adenomatous polyposis coli and hypoxia-inducible factor-1α have an antagonistic connection. Mol Biol Cell 21:3630–3638

    Article  PubMed  CAS  Google Scholar 

  38. Raica M, Cimpeana AM, Ribatti D (2009) Angiogenesis in pre-malignant conditions. Eur J Cancer 45:1924–1934

    Article  PubMed  CAS  Google Scholar 

  39. Silva BB, Santos AR, Pires CG et al (2009) Effect of raloxifene on vascular endothelial growth factor expression in breast carcinomas of postmenopausal women. Cell Prolif 42:506–510

    Article  PubMed  Google Scholar 

  40. Giatromanolaki A, Koukourakis MI, Sivridis E et al (2000) Coexpression of MUC1 glycoprotein with multiple angiogenic factors in non-small cell lung cancer suggests coactivation of angiogenic and migration pathways. Clin Cancer Res 6:1917–1921

    PubMed  CAS  Google Scholar 

  41. Bluff JE, Menakuru SR, Cross SS et al (2009) Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br J Cancer 101:666–672

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the technical assistance of Deisy Mara da Silva and Laura Midori Kawasse.

Conflicts of interest

We declare that we have no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alfredo Ribeiro-Silva.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zanetti, J.S., Soave, D.F., Oliveira-Costa, J.P. et al. The role of tumor hypoxia in MUC1-positive breast carcinomas. Virchows Arch 459, 367–375 (2011). https://doi.org/10.1007/s00428-011-1142-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-011-1142-6

Keywords

Navigation