Skip to main content
SpringerLink
Log in

Necrosis and Hypoxia in Invasive Breast Carcinoma

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

Abstract

To investigate the relation between necrosis and hypoxia in breast cancer we examined the expression of hypoxia-associated markers HIF1, CA IX and GLUT1 by immunohistochemistry in 97 invasive ductal carcinomas. This selected series comprised 48 tumors with extensive necrosis and 49 control tumors without necrosis. Over 90% of necrotic and 30% of non-necrotic tumors expressed at least one hypoxia marker. We also observed expression of hypoxia associated markers in tumor stroma. Examination of primary human breast fibroblasts in vitro confirmed that CA IX mRNA and protein can be induced by hypoxia. Survival analysis of 53 cases found that the subset of tumors with stromal hypoxia exhibit better prognosis (p = 0.027). Our results indicate that necrosis is often accompanied by hypoxia but that hypoxia without necrosis may also be a frequent occurrence. The use of several hypoxia markers may identify a continuum of hypoxia in tumors, which can be sub-classified by different co-expression patterns. We conclude that stromal and epithelial hypoxia may have different biological backgrounds and that stromal hypoxia may affect survival.

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

Similar content being viewed by others

References

  1. Parkkila S, Rajaniemi H, Parkkila AK, Kivela J, Waheed A, Pastorekova S, Pastorek J, Sly WS: Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci USA 97: 2220–2224, 2000

    Google Scholar 

  2. Koukourakis MI, Giatromanolaki A, Skarlatos J, Corti L, Blandamura S, Piazza M, Gatter KC, Harris AL: Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy. Cancer Res 61: 1830–1832, 2001

    Google Scholar 

  3. Bussolati G, Bongiovanni M, Cassoni P, Sapino A: Assessment of necrosis and hypoxia in ductal carcinoma in situ of the breast: basis for a new classification. Virchows Arch 437: 360–364, 2000

    Google Scholar 

  4. Dewhirst MW: Concepts of oxygen transport at the microcirculatory level. Semin Radiat Oncol 8: 143–150, 1998

    Google Scholar 

  5. Vaupel P, Schlenger K, Knoop C, Hockel M: Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51: 3316–3322, 1991

    Google Scholar 

  6. Semenza GL: Hif-1, o(2), and the 3 phds. How animal cells signal hypoxia to the nucleus. Cell 107: 1–3, 2001

    Google Scholar 

  7. Smith TA: Facilitative glucose transporter expression in human cancer tissue. Br J Biomed Sci 56: 285–292, 1999

    Google Scholar 

  8. Sly WS: The membrane carbonic anhydrases: from CO2 transport to tumour markers. In: Chegwidden WR (ed.) The Carbonic Anhydrases, Birkhauser, New Horizons,Basel, Boston, Berlin, 2000, pp 65–104

    Google Scholar 

  9. Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158: 905–919, 2001

    Google Scholar 

  10. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, Abeloff MD, Simons JW, van Diest PJ, van der WE: Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 93: 309–314, 2001

    Google Scholar 

  11. Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, Harris AL: Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19: 3660–3668, 2001

    Google Scholar 

  12. Younes M, Brown RW, Mody DR, Fernandez L, Laucirica R: GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res 15: 2895–2898, 1995

    Google Scholar 

  13. Pastorekova S, Zavadova Z, Kostal M, Babusikova O, Zavada J: A novel quasi-viral agent, MaTu, is a two-component system. Virology 187: 620–626, 1992

    Google Scholar 

  14. Kaluz S, Kaluzova M, Chrastina A, Olive PL, Pastorekova S, Pastorek J, Lerman MI, Stanbridge EJ: Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3_-kinase. Cancer Res 62: 4469–4477, 2002

    Google Scholar 

  15. Emerman JT, Stingl J, Petersen A, Shpall EJ, Eaves CJ: Selective growth of freshly isolated human breast epithelial cells cultured at low concentrations in the presence or absence of bone marrow cells. Breast Cancer Res Treat 41: 147–159, 1996

    Google Scholar 

  16. Strange KS, Wilkinson D, Emerman JT: Mitogenic properties of insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and epidermal growth factor on human breast epithelial cells in primary culture. Breast Cancer Res Treat 75: 203–212, 2002

    Google Scholar 

  17. Ramanujan S, Koenig GC, Padera TP, Stoll BR, Jain RK: Local imbalance of proangiogenic and antiangiogenic factors: a potential mechanism of focal necrosis and dormancy in tumors. Cancer Res 60: 1442–1448, 2000

    Google Scholar 

  18. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M: Induction of HIF-1alpha in response to hypoxia is instantaneous. FASEB J 15: 1312–1314, 2001

    Google Scholar 

  19. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J: p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274: 32631–32637, 1999

    Google Scholar 

  20. Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL: Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60: 7075–7083, 2000

    Google Scholar 

  21. Bruckner BA, Ammini CV, Otal MP, Raizada MK, Stacpoole PW: Regulation of brain glucose transporters by glucose and oxygen deprivation. Metabolism 48: 422–431, 1999

    Google Scholar 

  22. Kaluzova M, Pastorekova S, Svastova E, Pastorek J, Stanbridge EJ, Kaluz S: Characterization of the MN/CA 9 promoter proximal region: a role for specificity protein (SP) and activator protein 1 (AP1) factors. Biochem J 359: 669–677, 2001

    Google Scholar 

  23. Michiels C, Minet E, Michel G, Mottet D, Piret JP, Raes M: HIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases. IUBMB Life 52: 49–53, 2001

    Google Scholar 

  24. Laderoute KR, Calaoagan JM, Gustafson-Brown C, Knapp AM, Li GC, Mendonca HL, Ryan HE, Wang Z, Johnson RS: The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol Cell Biol 22: 2515–2523, 2002

    Google Scholar 

  25. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59: 5830–5835, 1999

    Google Scholar 

  26. Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G: Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8: 1831–1837, 2002

    Google Scholar 

  27. Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK: Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61: 6020–6024, 2001

    Google Scholar 

  28. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B: Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 17: 5085–5094, 1998

    Google Scholar 

  29. Bartosova M, Parkkila S, Pohlodek K, Karttunen TJ, Galbavy S, Mucha V, Harris AL, Pastorek J, Pastorekova S: Expression of carbonic anhydrase IX in breast is associated with malignant tissues and is related to overexpression of c-erbB2. J Pathol 197: 314–321, 2002

    Google Scholar 

  30. Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, West CM: Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61: 6394–6399, 2001

    Google Scholar 

  31. Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, Harris AL: Expression of hypoxiainducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 61: 7992–7998, 2001

    Google Scholar 

  32. Hasebe T, Sasaki S, Imoto S, Mukai K, Yokose T, Ochiai A: Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study. Mod Pathol 15: 502–516, 2002

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Department of Pathology, University of Manitoba, Winnipeg, MB, Canada

    Ladislav Tomes, Ethan Emberley, Yulian Niu, Sandra Troup & Peter H. Watson

  2. Slovak Academy of Sciences, Institute of Virology, Bratislava, Slovak Republic

    Jaromir Pastorek

  3. Department of Anatomy, University of British Columbia, Vancouver, BC, Canada

    Karen Strange

  4. Cancer Research UK Molecular Oncology Laboratory, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK

    Adrian Harris

Authors
  1. Ladislav Tomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ethan Emberley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yulian Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandra Troup
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaromir Pastorek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen Strange
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adrian Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter H. Watson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tomes, L., Emberley, E., Niu, Y. et al. Necrosis and Hypoxia in Invasive Breast Carcinoma. Breast Cancer Res Treat 81, 61–69 (2003). https://doi.org/10.1023/A:1025476722493

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025476722493

Search

Navigation