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Breast Cancer Research and Treatment

, Volume 56, Issue 2, pp 143–149 | Cite as

Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade

  • Walter Tschugguel
  • Christian Schneeberger
  • Gertrud Unfried
  • Klaus Czerwenka
  • Wolfgang Weninger
  • Michael Mildner
  • Doris M. Gruber
  • Michael O. Sator
  • Thomas Waldhör
  • Johannes C. Huber
Article

Abstract

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS + epithelial cells or total epithelial cells was 69 ± 16% (n=50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62 ± 20 (n=40), compared to 12 ± 9 (n=40) in samples of grade III carcinomas (P < 0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n=4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor’s metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.

breast cancer immunohistochemistry nitric oxide synthases 

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References

  1. 1.
    Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142, 1991Google Scholar
  2. 2.
    Knowles RG, Moncada S: Nitric oxide synthase in mammals. Biochem J 298: 249–258, 1994Google Scholar
  3. 3.
    Robbins RA, Barnes PJ, Springall DR, Warren JB, Kwon OJ, Buttery LD, Wilson AJ, Gellner DA, Polak JM: Expression of inducible nitric oxide synthase in human lung epithelial cells. Biochem Biophys Res Comm 203: 209–218, 1994Google Scholar
  4. 4.
    Bloom HJG, Richardson WW: Histologic grading and prognosis in breast cancer. A study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11: 359–377, 1957Google Scholar
  5. 5.
    Thomsen LL, Miles DW, Happerfield L, Bobrow LG, Knowles RG, Moncada S: Nitric oxide synthase activity in human breast cancer. Br J Cancer 72: 41–44, 1995Google Scholar
  6. 6.
    Tschugguel W, Knogler W, Czerwenka K, Mildner M, Weninger W, Zeillinger R, Huber JC: Presence of endothelial calcium-dependent nitric oxide synthase in breast apocrine metaplasia. Br J Cancer 74: 1423–1426, 1996Google Scholar
  7. 7.
    Konturek SJ, Brzozowski T, Majka J, Pyto-Polonczyk J, Stachura J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol 239: 215–217, 1993Google Scholar
  8. 8.
    Macchiarini P, Fontanini G, Hardin MJ, Squartini F, Angeletti CA: Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet 340: 145–146, 1992Google Scholar
  9. 9.
    Brawer MK, Deering RE, Brown M, Preston SD, Bigler SA: Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73: 678–687, 1994Google Scholar
  10. 10.
    Jenkins DC, Charles IG. Thomsen LL, Moss DW, Holmes LS, Baylis SA, Rhodes P, Westmore K, Emson PC, Moncada S: Roles of nitric oxide in tumour growth. Proc Natl Acad Sci USA 92: 4392–4396, 1995Google Scholar
  11. 11.
    Xie K, Huang S, Dong Z, Juang SH, Gutman M, Xie Q, Nathan C, Fiedler IJ: Transfection with the inducible nitric oxide synthase gene suppresses tumorigenicity and abrogates metastasis by K-1735 murine melanoma cells. J ExpMed 181: 1333–1343, 1995Google Scholar
  12. 12.
    Xie K, Huang S, Dong Z, Gutman M, Fidler IJ: Direct correlation between expression of endogenous inducible nitric oxide synthase and regression of M5076 reticulum cell sarcoma hepatic metastases in mice treated with liposomes containing lipopeptide CGP 31362. Cancer Res 55: 3123–3131, 1995Google Scholar
  13. 13.
    Thomsen LL, Scott JMJ, Topley P, Knowles RG, Keerie AJ, Frend AJ: Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. Cancer Res 57: 3300–3304, 1997Google Scholar
  14. 14.
    Hermanek P, Scheibe O, Spiessl B, Wagner G: UICC International Union Against Cancer: TNM Klassifikation maligner Tumoren. Springer-Verlag, Berlin, Heidelberg, New York, London, Paris, Tokyo, 1987, pp 100–106Google Scholar
  15. 15.
    Tschugguel W, Schneeberger C, Unfried G, Czerwenka K, Weninger W, Mildner M, Bishop JR, Huber JC: Induction of inducible nitric oxide synthase expression in human secretory endometrium. Hum Reprod 13: 436–444, 1998Google Scholar
  16. 16.
    Godfroid B, Geuskens M, Dupressoir T, Parent I, Szpirer C: Cytokeratins are exposed to the outer surface of established human mammary carcinoma cells. J Cell Sci 99: 595–607, 1991Google Scholar
  17. 17.
    Hembrough TA, Vasudevan J, Allietta MM, Glass WF2nd, Gonias SL: A cytokeratin 8-like protein with plasminogenbinding activity is present on the external surface of hepatocytes, HepG2 cells and breast carcinoma cell lines. J Cell Sci 108: 1071–1082, 1995Google Scholar
  18. 18.
    Horak ER, Leek R, Klenk N, Lejeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL: Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastasis and survival in breast cancer. Lancet 340: 1120–1124, 1992Google Scholar
  19. 19.
    Zeillinger R, Tantscher E, Schneeberger C, Tschugguel W, Eder S, Sliutz G, Huber JC: Simultaneous expression of nitric oxide synthase and estrogen receptor in human breast cancer cell lines. Breast Cancer Res Treat 40: 205–207, 1996Google Scholar
  20. 20.
    Stuehr DJ, Nathan CF: Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med 169: 1543–1555, 1989Google Scholar
  21. 21.
    Cui S, Reichner JS, Mateo RB, Albina JE: Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or-independent mechanisms. Cancer Res 54: 2462–2467, 1994Google Scholar
  22. 22.
    Farais-Eisner R, Sherman MP, Aeberhard E, Chaudhuri G: Nitric oxide is an important mediator for tumoricidal activity in vivo. Proc Natl Acad Sci USA 91: 9407–9411, 1994Google Scholar
  23. 23.
    Thomsen LL, Lawton FG, Knowles RG, Beesley JE, RiverosMoreno V, Moncada S: Nitric oxide synthase activity in human gynecological cancer. Cancer Res 54: 1352–1354, 1994Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Walter Tschugguel
    • 1
  • Christian Schneeberger
    • 1
  • Gertrud Unfried
    • 1
  • Klaus Czerwenka
    • 2
  • Wolfgang Weninger
    • 3
  • Michael Mildner
    • 3
  • Doris M. Gruber
    • 1
  • Michael O. Sator
    • 1
  • Thomas Waldhör
    • 4
  • Johannes C. Huber
    • 1
  1. 1.Departments of Gynecology and Obstetrics, Division of Gynecological Endocrinology and Reproductive MedicineUSA
  2. 2.Departments of Clinical PathologyUniversity of Vienna, School of MedicineViennaAustria
  3. 3.Departments of DermatologyUniversity of Vienna, School of MedicineViennaAustria
  4. 4.Departments of Institute Tumor Biology and Cancer ResearchUniversity of Vienna, School of MedicineViennaAustria

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