ORIGINAL ARTICLE

Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer

C Costa¹, R Soares², J S Reis-Filho¹, D Leitão¹, I Amendoeira³, F C Schmitt⁴

¹ Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias S/N, 4200-Porto, Portugal
² Molecular Oncology Unit, Department of Pathology, Instituto Português de Oncologia do Porto, 4200-Porto, Portugal
³ Department of Pathology, Hospital de São João, 4200-Porto, Portugal
⁴ Medical Faculty, Porto University, Porto, Portugal

Correspondence to:
Correspondence to:
Dr F C Schmitt, Instituto de Patologia e Immunologia Molecular da Universidade do Porto, Rua Dr. Roberto Frias, s/n, 4200 Porto, Portugal;
fernando.schmitt{at}ipatimup.pt

Aims: Cyclo-oxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis. COX-2 is induced by a wide variety of stimuli, and present during inflammation. COX-2 overexpression has been observed in colon, head and neck, lung, prostate, stomach, and breast cancer. In colon and gastric cancer, COX-2 expression was associated with angiogenesis. The aim of this study was to determine the relation between COX-2 expression and angiogenesis in breast cancer, and to correlate the expression of this enzyme with classic clinicopathological parameters.

Methods: COX-2 expression was investigated by immunohistochemistry and western blotting analysis. The expression of COX-2 was then related to age, histological grade, nodal status, oestrogen receptor status, p53 expression,c-erb-B2 overexpression, mitotic counts, MIB-1 labelling index, apoptotic index, sialyl-Tn expression, transforming growth factor expression, microvessel density, and disease free survival in 46 patients with invasive ductal breast carcinoma.

Results: By means of immunohistochemistry, COX-2 expression was detected in eight of the 46 carcinomas studied. Western blotting showed COX-2 protein expression in the same breast tumours, but not in normal adjacent tissues. The density of microvessels immunostained with anti-F-VIII related antigen was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03). In addition, COX-2 was significantly associated with the presence of sialyl-Tn expression (p = 0.02), lymph node metastasis (p = 0.03), a high apoptotic index (p = 0.03), and a short disease free survival (p = 0.03) in univariate analyses.

Conclusions: These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.

Keywords: cyclo-oxygenase 2; angiogenesis; breast cancer

Abbreviations: COX, cyclo-oxygenase; ER, oestrogen receptor; F-VIII, factor VIII related antigen; HPF, high power field; STn, sialyl Tn; TGF-, transforming growth factor ; VEGF, vascular endothelial growth factor

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Lavalle, G. E., Bertagnolli, A. C., Tavares, W. L. F., Cassali, G. D. (2009). Cox-2 Expression in Canine Mammary Carcinomas: Correlation with Angiogenesis and Overall Survival. Vet Pathol 46: 1275-1280 [Abstract] [Full Text]  
• Kim, D.-H., Kim, J.-H., Kim, E.-H., Na, H.-K., Cha, Y.-N., Chung, J. H., Surh, Y.-J. (2009). 15-Deoxy-{Delta}12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS. Carcinogenesis 30: 645-654 [Abstract] [Full Text]  
• Park, S.-A., Na, H.-K., Kim, E.-H., Cha, Y.-N., Surh, Y.-J. (2009). 4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of I{kappa}B Kinase: Potential Role of Reactive Oxygen Species. Cancer Res. 69: 2416-2424 [Abstract] [Full Text]  
• Penault-Llorca, F., Abrial, C., Raoelfils, I., Chollet, P., Cayre, A., Mouret-Reynier, M.-A., Thivat, E., Mishellany, F., Gimbergues, P., Durando, X. (2008). Changes and Predictive and Prognostic Value of the Mitotic Index, Ki-67, Cyclin D1, and Cyclo-oxygenase-2 in 710 Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. The Oncologist 13: 1235-1245 [Abstract] [Full Text]  
• Pan, M.-R., Hou, M.-F., Chang, H.-C., Hung, W.-C. (2008). Cyclooxygenase-2 Up-regulates CCR7 via EP2/EP4 Receptor Signaling Pathways to Enhance Lymphatic Invasion of Breast Cancer Cells. J. Biol. Chem. 283: 11155-11163 [Abstract] [Full Text]  
• Wu, J. M., Fackler, M. J., Halushka, M. K., Molavi, D. W., Taylor, M. E., Teo, W. W., Griffin, C., Fetting, J., Davidson, N. E., De Marzo, A. M., Hicks, J. L., Chitale, D., Ladanyi, M., Sukumar, S., Argani, P. (2008). Heterogeneity of Breast Cancer Metastases: Comparison of Therapeutic Target Expression and Promoter Methylation Between Primary Tumors and Their Multifocal Metastases. Clin. Cancer Res. 14: 1938-1946 [Abstract] [Full Text]  
• Visscher, D. W., Pankratz, V. S., Santisteban, M., Reynolds, C., Ristimaki, A., Vierkant, R. A., Lingle, W. L., Frost, M. H., Hartmann, L. C. (2008). Association Between Cyclooxygenase-2 Expression in Atypical Hyperplasia and Risk of Breast Cancer. JNCI J Natl Cancer Inst 100: 421-427 [Abstract] [Full Text]  
• Mitchell, J. A., Lucas, R., Vojnovic, I., Hasan, K., Pepper, J. R., Warner, T. D. (2006). Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events. FASEB J. 20: 2468-2475 [Abstract] [Full Text]  
• Schmitz, K J, Callies, R, Wohlschlaeger, J, Kimmig, R, Otterbach, F, Bohr, J, Lee, H-S, Takeda, A, Schmid, K W, Baba, H A (2006). Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with Her-2/neu signalling pathways. J. Clin. Pathol. 59: 685-691 [Abstract] [Full Text]  
• Siironen, P., Ristimaki, A., Narko, K., Nordling, S., Louhimo, J., Andersson, S., Haapiainen, R., Haglund, C. (2006). VEGF-C and COX-2 expression in papillary thyroid cancer.. Endocr Relat Cancer 13: 465-473 [Abstract] [Full Text]  
• Hiraga, T., Myoui, A., Choi, M. E., Yoshikawa, H., Yoneda, T. (2006). Stimulation of Cyclooxygenase-2 Expression by Bone-Derived Transforming Growth Factor-{beta} Enhances Bone Metastases in Breast Cancer. Cancer Res. 66: 2067-2073 [Abstract] [Full Text]  
• Howe, L. R., Chang, S.-H., Tolle, K. C., Dillon, R., Young, L. J.T., Cardiff, R. D., Newman, R. A., Yang, P., Thaler, H. T., Muller, W. J., Hudis, C., Brown, A. M.C., Hla, T., Subbaramaiah, K., Dannenberg, A. J. (2005). HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice. Cancer Res. 65: 10113-10119 [Abstract] [Full Text]  
• Heller, D. A., Clifford, C. A., Goldschmidt, M. H., Holt, D. E., Manfredi, M. J., Sorenmo, K. U. (2005). Assessment of Cyclooxygenase-2 Expression in Canine Hemangiosarcoma, Histiocytic Sarcoma, and Mast Cell Tumor. Vet Pathol 42: 350-353 [Abstract] [Full Text]  
• Tan, K-B, Putti, T C (2005). Cyclooxygenase 2 expression in nasopharyngeal carcinoma: immunohistochemical findings and potential implications. J. Clin. Pathol. 58: 535-538 [Abstract] [Full Text]  
• Kong, G., Kim, H.-T., Wu, K., DeNardo, D., Hilsenbeck, S. G., Xu, X.-C., Lamph, W. W., Bissonnette, R., Dannenberg, A. J., Brown, P. H. (2005). The Retinoid X Receptor-Selective Retinoid, LGD1069, Down-regulates Cyclooxygenase-2 Expression in Human Breast Cells through Transcription Factor Crosstalk: Implications for Molecular-Based Chemoprevention. Cancer Res. 65: 3462-3469 [Abstract] [Full Text]  
• Ilsley, J. N.M., Nakanishi, M., Flynn, C., Belinsky, G. S., De Guise, S., Adib, J. N., Dobrowsky, R. T., Bonventre, J. V., Rosenberg, D. W. (2005). Cytoplasmic Phospholipase A2 Deletion Enhances Colon Tumorigenesis. Cancer Res. 65: 2636-2643 [Abstract] [Full Text]  
• Hicklin, D. J., Ellis, L. M. (2005). Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis. JCO 23: 1011-1027 [Abstract] [Full Text]  
• Holland, C. M., Saidi, S. A., Evans, A. L., Sharkey, A. M., Latimer, J. A., Crawford, R. A.F., Charnock-Jones, D. S., Print, C. G., Smith, S. K. (2004). Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets. Molecular Cancer Therapeutics 3: 993-1001 [Abstract] [Full Text]  
• Ng, S. S. W., Gutschow, M., Weiss, M., Hauschildt, S., Teubert, U., Hecker, T. K., Luzzio, F. A., Kruger, E. A., Eger, K., Figg, W. D. (2003). Antiangiogenic Activity of N-substituted and Tetrafluorinated Thalidomide Analogues. Cancer Res. 63: 3189-3194 [Abstract] [Full Text]