Skip to main content
Top
Published in: Virchows Archiv 1/2005

01-07-2005 | Original Article

Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of 151 cases

Authors: Asiye Safak Bulut, Esra Erden, Serpil Dizbay Sak, Hatice Doruk, Nazmiye Kursun, Dilek Dincol

Published in: Virchows Archiv | Issue 1/2005

Login to get access

Abstract

The role of calcium independent inducible nitric oxide synthase (iNOS) in breast carcinoma is controversial, and the implications of iNOS expression on prognosis are not known. In this study, we aimed to investigate the significance of immunohistochemical iNOS expression in 100 invasive ductal carcinomas. In addition, 11 normal breast tissues, 20 cases of usual ductal hyperplasias (UDHs) and 20 fibroadenomas were included. We found that 78% of malignant and 75% of benign cases showed iNOS immunoreactivity. However, the intensity and the quantity of iNOS expression were significantly higher in the cancer group when compared with benign breasts (P<0.001), suggesting a role of iNOS in breast carcinogenesis. We were unable to show a correlation between iNOS expression and tumor grade, axillary lymph node status, and estrogen receptor expression. In 50 axilla negative cases having 5–12 years follow-up, disease free survival (DFS) rate was significantly lower in cases showing strong iNOS expression (P=0.05). As strong iNOS expression was correlated with short DFS, we concluded that further studies would be necessary to elucidate if iNOS expression might be a useful prognostic marker in breast carcinoma, especially in the axilla negative group.
Literature
1.
go back to reference Aaltomaa SH, Lipponen PK, Viitanen J, Kankkunen JP, Ala-Opas MY, Kosma VM (2000) The prognostic value of inducible nitric oxide synthase in local prostate cancer. BJU Int 86:234–239CrossRefPubMed Aaltomaa SH, Lipponen PK, Viitanen J, Kankkunen JP, Ala-Opas MY, Kosma VM (2000) The prognostic value of inducible nitric oxide synthase in local prostate cancer. BJU Int 86:234–239CrossRefPubMed
2.
go back to reference Brennan PA, Sharma S, Bowden JR, Umar T (2003) Expression of inducible nitric oxide synthase in bone metastasis. Eur J Surg Oncol 27:619–623 Brennan PA, Sharma S, Bowden JR, Umar T (2003) Expression of inducible nitric oxide synthase in bone metastasis. Eur J Surg Oncol 27:619–623
3.
go back to reference Chinje EJ, Stratford IJ (1997) Role of nitric oxide in growth of solid tumors: a balancing act. Essays Biochem 32:61–72PubMed Chinje EJ, Stratford IJ (1997) Role of nitric oxide in growth of solid tumors: a balancing act. Essays Biochem 32:61–72PubMed
4.
go back to reference Choe W, Kim S, Hwang TS, Lee SS (2003) Expression of inducible nitric oxide synthase in thyroid neoplasms: immunohistochemical and molecular analysis. Pathol Int 53:434–439CrossRefPubMed Choe W, Kim S, Hwang TS, Lee SS (2003) Expression of inducible nitric oxide synthase in thyroid neoplasms: immunohistochemical and molecular analysis. Pathol Int 53:434–439CrossRefPubMed
5.
go back to reference Duenas-Gonzales A, Isales CM, Abad-Hernandez MD, Gonzalez-Sarmiento R, Sangueza O, Rodriguez-Commes J (1997) Expression of inducible nitric oxide synthase in breast cancer correlates with metastatic disease. Mod Path 10:645–649 Duenas-Gonzales A, Isales CM, Abad-Hernandez MD, Gonzalez-Sarmiento R, Sangueza O, Rodriguez-Commes J (1997) Expression of inducible nitric oxide synthase in breast cancer correlates with metastatic disease. Mod Path 10:645–649
6.
go back to reference Ekmekçioğlu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6:4768–4775 Ekmekçioğlu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6:4768–4775
7.
go back to reference Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994) Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 23(part 2):1121–1131PubMed Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H (1994) Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension 23(part 2):1121–1131PubMed
8.
go back to reference Hong SK, Gul YA, Ithnin H, Talib A, Seow HF (2004) Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 and iNOS inhibitors for treatment in Malaysia. Asian J Surg 27:10–17PubMed Hong SK, Gul YA, Ithnin H, Talib A, Seow HF (2004) Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 and iNOS inhibitors for treatment in Malaysia. Asian J Surg 27:10–17PubMed
9.
go back to reference Huang Z, Zeng ZY, Peng HW, Xia LP, Hou JH (2003) Inducible nitric oxide synthase and basic fibroblast growth factor expression as prognostic factors in supraglottic squamous cell carcinoma. Aizheng 22:978–981PubMed Huang Z, Zeng ZY, Peng HW, Xia LP, Hou JH (2003) Inducible nitric oxide synthase and basic fibroblast growth factor expression as prognostic factors in supraglottic squamous cell carcinoma. Aizheng 22:978–981PubMed
10.
go back to reference Jadeski LC, Hum KO, Chakraborty C, Lala PK (2000) Nitric oxide promotes murine mammary tumor growth and metastasis by stimulating tumor cell migration, invasiveness and angiogenesis. Int J Cancer 86:30–39CrossRefPubMed Jadeski LC, Hum KO, Chakraborty C, Lala PK (2000) Nitric oxide promotes murine mammary tumor growth and metastasis by stimulating tumor cell migration, invasiveness and angiogenesis. Int J Cancer 86:30–39CrossRefPubMed
11.
go back to reference Kato S, Esumi H, Hirano A, Kato M, Asayama K, Ohama E (2003) Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationship of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein. Acta Neuropathol 105:333–340PubMed Kato S, Esumi H, Hirano A, Kato M, Asayama K, Ohama E (2003) Immunohistochemical expression of inducible nitric oxide synthase (iNOS) in human brain tumors: relationship of iNOS to superoxide dismutase (SOD) proteins (SOD1 and SOD2), Ki-67 antigen (MIB-1) and p53 protein. Acta Neuropathol 105:333–340PubMed
12.
go back to reference Kitano H, Kitanishi T, Nakanishi Y, Suzuki M, Takeuchi E, Yazawa Y, Kitajima K, Kimura H, Tooyama I (1999) Expression of inducible nitric oxide synthase in human thyroid papillary carcinomas. Thyroid 9:113–117PubMed Kitano H, Kitanishi T, Nakanishi Y, Suzuki M, Takeuchi E, Yazawa Y, Kitajima K, Kimura H, Tooyama I (1999) Expression of inducible nitric oxide synthase in human thyroid papillary carcinomas. Thyroid 9:113–117PubMed
13.
go back to reference Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82:1897–1903 Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82:1897–1903
14.
go back to reference Kojima M, Morisaki T, Tsukahara Y, Uchiyama A, Matsunari Y, Mibu R, Tanaka M (1999) Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue. J Surg Oncol 70:222–229CrossRefPubMed Kojima M, Morisaki T, Tsukahara Y, Uchiyama A, Matsunari Y, Mibu R, Tanaka M (1999) Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue. J Surg Oncol 70:222–229CrossRefPubMed
15.
go back to reference Kong G, Kim EK, Kim WS, Lee KT, Lee YW, Lee JK, Paik SW, Rhee JC (2002) Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer. J Gastroenterol Hepatol 17:914–921CrossRefPubMed Kong G, Kim EK, Kim WS, Lee KT, Lee YW, Lee JK, Paik SW, Rhee JC (2002) Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer. J Gastroenterol Hepatol 17:914–921CrossRefPubMed
16.
go back to reference Lagares-Garcia JA, Moore RA, Collier B, Heggere M, Diaz F, Qian F (2001) Nitric oxide synthase as a marker in colorectal carcinoma. Am Surgeon 67:709–713PubMed Lagares-Garcia JA, Moore RA, Collier B, Heggere M, Diaz F, Qian F (2001) Nitric oxide synthase as a marker in colorectal carcinoma. Am Surgeon 67:709–713PubMed
17.
go back to reference Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R (2000) Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol 53:634–635CrossRefPubMed Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R (2000) Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol 53:634–635CrossRefPubMed
18.
go back to reference Liu CY, Wang CH, Chen TC, Lin HC, Yu CT, Kuo HP (1998) Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer 78:534–541 Liu CY, Wang CH, Chen TC, Lin HC, Yu CT, Kuo HP (1998) Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer 78:534–541
19.
go back to reference Loibl S, Von Minckwitz G, Weber S, Sinn HP, Schini-Kerth VB, Lobysheva I, Nepveu F, Wolf G, Strebhardt K, Kaufmann M (2002) Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy. Cancer 95:1191–1198 Loibl S, Von Minckwitz G, Weber S, Sinn HP, Schini-Kerth VB, Lobysheva I, Nepveu F, Wolf G, Strebhardt K, Kaufmann M (2002) Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy. Cancer 95:1191–1198
20.
go back to reference Loibl S, Buck A, Strank C, von Minckwitz G, Roller M, Sinn HP, Schini-Kerth V, Solbach C, Strebhardt K, Kaufmann M (2005) The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur J Cancer 41:265–271CrossRefPubMed Loibl S, Buck A, Strank C, von Minckwitz G, Roller M, Sinn HP, Schini-Kerth V, Solbach C, Strebhardt K, Kaufmann M (2005) The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur J Cancer 41:265–271CrossRefPubMed
21.
go back to reference Niu X-J, Wang Z-R, Wu S-L, Geng Z-M, Zhang Y-F, Qing L (2004) Relationship between inducible nitric oxide synthase expression and angiogenesis in primary gallbladder carcinoma tissue. World J Gastroenterol 10:725–728PubMed Niu X-J, Wang Z-R, Wu S-L, Geng Z-M, Zhang Y-F, Qing L (2004) Relationship between inducible nitric oxide synthase expression and angiogenesis in primary gallbladder carcinoma tissue. World J Gastroenterol 10:725–728PubMed
22.
go back to reference Nozoe T, Yasuda M, Honda M, Inutsuka S, Korenaga D (2002) Immunohistochemical expression of cytokine induced nitric oxide synthase in colorectal carcinoma. Oncol Rep 9:521–524PubMed Nozoe T, Yasuda M, Honda M, Inutsuka S, Korenaga D (2002) Immunohistochemical expression of cytokine induced nitric oxide synthase in colorectal carcinoma. Oncol Rep 9:521–524PubMed
23.
go back to reference Oka K, Suzuki Y, Iida H, Nakano T (2003) PD-ECGF positivity correlates with better survival, while iNOS has no predictive value for cervical carcinomas treated with radiotherapy. Int J Radiat Oncol Biol Phys 57:217–221CrossRefPubMed Oka K, Suzuki Y, Iida H, Nakano T (2003) PD-ECGF positivity correlates with better survival, while iNOS has no predictive value for cervical carcinomas treated with radiotherapy. Int J Radiat Oncol Biol Phys 57:217–221CrossRefPubMed
24.
go back to reference Peng JP, Zheng S, Xiao ZX, Zhang SZ (2003) Inducible nitric oxide synthase expression is related to angiogenesis, bcl-2 and cell proliferation in hepatocellular carcinoma. J Zhejiang Univ Sci 4:221–227PubMed Peng JP, Zheng S, Xiao ZX, Zhang SZ (2003) Inducible nitric oxide synthase expression is related to angiogenesis, bcl-2 and cell proliferation in hepatocellular carcinoma. J Zhejiang Univ Sci 4:221–227PubMed
25.
go back to reference Puhakka A, Kinnula V, Napankangas U, Saily M, Koistinen M, Paakko P, Soini Y (2003) High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma. Acta Pathol Microbiol Immunol Scand 111:1137–1146 Puhakka A, Kinnula V, Napankangas U, Saily M, Koistinen M, Paakko P, Soini Y (2003) High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma. Acta Pathol Microbiol Immunol Scand 111:1137–1146
26.
go back to reference Pukkila MJ, Kellokoski JK, Virtaniemi JA, Kumpulainen EJ, Johansson RT, Halonen PM, Kosunen AS, Nuutinen J, Kosma VM (2002) Inducible nitric oxide synthase expression in pharyngeal squamous cell carcinoma: relation to p53 expression, clinicopathological data, and survival. Laryngoscope 112:1084–1088CrossRefPubMed Pukkila MJ, Kellokoski JK, Virtaniemi JA, Kumpulainen EJ, Johansson RT, Halonen PM, Kosunen AS, Nuutinen J, Kosma VM (2002) Inducible nitric oxide synthase expression in pharyngeal squamous cell carcinoma: relation to p53 expression, clinicopathological data, and survival. Laryngoscope 112:1084–1088CrossRefPubMed
27.
go back to reference Raspollini MR, Amunni G, Villanucci A, Boddi V, Baroni G, Taddei A, Taddei GL (2003) Expression of inducible nitric oxide synthase and cyclooxygenase in ovarian cancer: correlation with clinical outcome. Gynecol Oncol 92:806–812CrossRef Raspollini MR, Amunni G, Villanucci A, Boddi V, Baroni G, Taddei A, Taddei GL (2003) Expression of inducible nitric oxide synthase and cyclooxygenase in ovarian cancer: correlation with clinical outcome. Gynecol Oncol 92:806–812CrossRef
28.
go back to reference Reveneau S, Arnould R, Jolimoy G, Hilpert S, Lejeune P, Saint-Giorgio V, Belichard C, Jeannin JF (1999) Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors. Lab Invest 79:1215–1225PubMed Reveneau S, Arnould R, Jolimoy G, Hilpert S, Lejeune P, Saint-Giorgio V, Belichard C, Jeannin JF (1999) Nitric oxide synthase in human breast cancer is associated with tumor grade, proliferation rate, and expression of progesterone receptors. Lab Invest 79:1215–1225PubMed
29.
go back to reference Ropponen KM, Kellokoski JK, Lipponen PK, Eskelinen MJ, Alanne L, Alhava EM, Kosma VM (2000) Expression of inducible nitric oxide synthase in colorectal cancer and its association with prognosis. Scand J Gastroenterol 35:1204–1211CrossRefPubMed Ropponen KM, Kellokoski JK, Lipponen PK, Eskelinen MJ, Alanne L, Alhava EM, Kosma VM (2000) Expression of inducible nitric oxide synthase in colorectal cancer and its association with prognosis. Scand J Gastroenterol 35:1204–1211CrossRefPubMed
30.
go back to reference Soini Y, Kahlos K, Puhakka A, Lakari E, Saily M, Paakko P, Kinnula V (2000) Expression of inducible nitric oxide synthase in healthy pleura and malignant mesothelioma. Br J Cancer 83:880–886 Soini Y, Kahlos K, Puhakka A, Lakari E, Saily M, Paakko P, Kinnula V (2000) Expression of inducible nitric oxide synthase in healthy pleura and malignant mesothelioma. Br J Cancer 83:880–886
31.
go back to reference Tanaka H, Kijima H, Tokunaga T, Tajima T, Himeno S, Kenmochi T, Oshiba G, Kise Y, Nishi T, Chino O, Shimada H, Machimura T, Tanaka M, Makuuchi M (1999) Frequent expression of inducible nitric oxide synthase in esophageal squamous cell carcinoma. Int J Oncol 14:1069–1071PubMed Tanaka H, Kijima H, Tokunaga T, Tajima T, Himeno S, Kenmochi T, Oshiba G, Kise Y, Nishi T, Chino O, Shimada H, Machimura T, Tanaka M, Makuuchi M (1999) Frequent expression of inducible nitric oxide synthase in esophageal squamous cell carcinoma. Int J Oncol 14:1069–1071PubMed
32.
go back to reference Tavassoli FA (1999) Ductal intraepithelial neoplasia. In: Tavassoli FA (ed) Pathology of the breast, 2nd edn. Appleton & Lange, Stamford, Connecticut, p 212 Tavassoli FA (1999) Ductal intraepithelial neoplasia. In: Tavassoli FA (ed) Pathology of the breast, 2nd edn. Appleton & Lange, Stamford, Connecticut, p 212
33.
go back to reference Tschugguel W, Schneeberger C, Unfried G, Czerwenka K, Weninger W, Mildner M, Gruber DM, Sator MO, Waldhör T, Huber JC (1999) Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. Breast Cancer Res Treat 56:145–151CrossRefPubMed Tschugguel W, Schneeberger C, Unfried G, Czerwenka K, Weninger W, Mildner M, Gruber DM, Sator MO, Waldhör T, Huber JC (1999) Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. Breast Cancer Res Treat 56:145–151CrossRefPubMed
34.
go back to reference Umar T, Bowden J, Cameron S, Willy PJ, Anand R, Baker Ilankoran V, Brennan PA (2003) Expression of inducible nitric oxide synthase in cutaneous adnexal tumors of the head and neck. Int J Oral Maxillofac Surg 32:534–538CrossRefPubMed Umar T, Bowden J, Cameron S, Willy PJ, Anand R, Baker Ilankoran V, Brennan PA (2003) Expression of inducible nitric oxide synthase in cutaneous adnexal tumors of the head and neck. Int J Oral Maxillofac Surg 32:534–538CrossRefPubMed
35.
go back to reference Vakkala M, Kahlos K, Lakari E, Paakko P, Kinnula V, Soini Y (2000) Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in-situ and invasive breast carcinomas. Clin Cancer Res 6:2408–2416 Vakkala M, Kahlos K, Lakari E, Paakko P, Kinnula V, Soini Y (2000) Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in-situ and invasive breast carcinomas. Clin Cancer Res 6:2408–2416
36.
go back to reference Vickers SM, MacMillan-Crow LA, Green M, Ellis C, Thomsen JA (1999) Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch Surg 134:245–251CrossRefPubMed Vickers SM, MacMillan-Crow LA, Green M, Ellis C, Thomsen JA (1999) Association of increased immunostaining for inducible nitric oxide synthase and nitrotyrosine with fibroblast growth factor transformation in pancreatic cancer. Arch Surg 134:245–251CrossRefPubMed
37.
go back to reference Wang J, Torbenson M, Wang Q, Ro JY, Becich M (2003) Expression of inducible nitric oxide synthase in paired neoplastic and non-neoplastic primary prostate cell cultures and prostatectomy specimen. Urol Oncol 21:117–122PubMed Wang J, Torbenson M, Wang Q, Ro JY, Becich M (2003) Expression of inducible nitric oxide synthase in paired neoplastic and non-neoplastic primary prostate cell cultures and prostatectomy specimen. Urol Oncol 21:117–122PubMed
38.
go back to reference Wolf H, Haeckel C, Roessner A (2000) Inducible nitric oxide synthase expression in human urinary bladder cancer. Virchows Arch 437:662–666CrossRefPubMed Wolf H, Haeckel C, Roessner A (2000) Inducible nitric oxide synthase expression in human urinary bladder cancer. Virchows Arch 437:662–666CrossRefPubMed
39.
go back to reference Yagihashi N, Kasajima H, Sugai S, Matsumoto K, Ebina Y, Morita T, Murakami T, Yagihashi S (2000) Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Arch 436:109–114PubMed Yagihashi N, Kasajima H, Sugai S, Matsumoto K, Ebina Y, Morita T, Murakami T, Yagihashi S (2000) Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Arch 436:109–114PubMed
40.
go back to reference Zhang M, Pan JW, Ren TR, Zhu YF, Han YJ, Kuhnel W (2003) Correlated expression of inducible nitric oxide synthase and p53, Bax in benign and malignant diseased gallbladder. Ann Anat 185:549–554PubMed Zhang M, Pan JW, Ren TR, Zhu YF, Han YJ, Kuhnel W (2003) Correlated expression of inducible nitric oxide synthase and p53, Bax in benign and malignant diseased gallbladder. Ann Anat 185:549–554PubMed
Metadata
Title
Significance of inducible nitric oxide synthase expression in benign and malignant breast epithelium: an immunohistochemical study of 151 cases
Authors
Asiye Safak Bulut
Esra Erden
Serpil Dizbay Sak
Hatice Doruk
Nazmiye Kursun
Dilek Dincol
Publication date
01-07-2005
Publisher
Springer-Verlag
Published in
Virchows Archiv / Issue 1/2005
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-005-1250-2

Other articles of this Issue 1/2005

Virchows Archiv 1/2005 Go to the issue