Skip to main content

Advertisement

Log in

Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study was to evaluate breast carcinomas for the expression of cyclooxygenase-2 (Cox-2) using a tissue microarray (TMA) and to determine its clinical and prognostic relevance.

Methods

We analyzed Cox-2 expression in 600 samples from 200 breast carcinomas immunohistochemically performing TMA technology and semiquantitative analysis. Results were correlated with various clinicopathological variables and follow-up data. Expression of estrogen receptor, progesterone receptor, Ki-67, and Her-2/neu-oncogene was analyzed and correlated with Cox-2 status.

Results

We observed a moderate or strong cytoplasmic staining for Cox-2 in 78 (40.6%) of breast carcinomas. Increased Cox-2 expression corresponded to higher pT stage (P=0.038), amplification of Her-2/neu (P=0.032), lymphovascular invasion (P=0.006), a high MIB-1 labeling index (LI) (P<0.001), and histological grading (P=0.013). We also observed an inverse relationship between strong Cox-2 expression and estrogen and progesterone receptor content of tumors (P=0.037 and P=0.010). However, we could not demonstrate a significant association between Cox-2 staining and overall survival or disease free survival time.

Conclusions

These results suggest that Cox-2 expression is significantly associated with less differentiated and more aggressive breast carcinomas and might therefore be a useful prognostic indicator as well as a target for therapy.

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.
Fig. 2A-F.
Fig. 3A-H.
Fig 4A,B.

Similar content being viewed by others

References

  • Alshafie GA, Abou-Issa HM, Seibert K, Harris RE (2000) Chemotherapeutic evaluation of celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol Rep 7:1377–1381

    CAS  PubMed  Google Scholar 

  • Altman DG (1995) Chi square test for trend. In: Practical statistics for medical research. Chapman & Hall, London, pp 261–265

  • Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS (2001) Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res 7:1410–1418

    CAS  PubMed  Google Scholar 

  • Bandyopadhyay GK, Imagawa W, Wallace D, Nandi S (1987) Linoleate metabolites enhance the in vitro proliferative response of mouse mammary epithelial cells to epidermal growth factor. J Biol Chem 262:2750–2756

    CAS  PubMed  Google Scholar 

  • Bankfalvi A, Navabi H, Bier B, Bocker W, Jasani B, Schmid KW (1994) Wet autoclave pretreatment for antigen retrieval in diagnostic immunohistochemistry. J Pathol 174:223–228

    CAS  PubMed  Google Scholar 

  • Bennett A, Charlier EM, McDonald AM, Simpson JS, Stamford IF, Zebro T (1977) Prostaglandins and breast cancer. Lancet 2:624–626

    CAS  PubMed  Google Scholar 

  • Cao QJ, Einstein MH, Anderson PS, Runowicz CD, Balorn R, Jones JG (2002) Expression of Cox-2, Ki-67, Cyclin D1, and P21 in endometrial endometrioid carcinomas. Int J Gynecol Pathol 21:147–154

    PubMed  Google Scholar 

  • Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC (2002) Cyclooxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol 55:429–434

    CAS  PubMed  Google Scholar 

  • Denkert C, Köbel M, Pest S, Koch I, Berger S, Schwabe M, Siegert A, Reles A, Klosterhalfen B, Hauptmann S (2002) Expression of cyclooxygenase-2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol 160:893–903

    CAS  PubMed  Google Scholar 

  • DeWitt DL, Smith WL (1988) Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence. Proc Natl Acad Sci USA 85:1412–1416

    CAS  PubMed  Google Scholar 

  • Eberhardt CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterol 107:1183–1188

    CAS  PubMed  Google Scholar 

  • Egan KM, Stampfer MJ, Giovannucci E, Rosner BA, Colditz GA (1996) Prospective study of regular aspirin use and the risk of breast cancer. J Natl Cancer Inst 88:988–993

    CAS  PubMed  Google Scholar 

  • Gupta RA, DuBois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1:11–21

    Article  CAS  PubMed  Google Scholar 

  • Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA (2002) Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res 62:1676–1681

    CAS  PubMed  Google Scholar 

  • Harris RE, Alshafie GA, Abou-Issa H, Seibert K (2000) Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60:2101–2103

    PubMed  Google Scholar 

  • Hla T, Neilson K (1992) Human cylcooxygenase-2 cDNA. Proc Natl Acad Sci USA 89:7384–7388

    CAS  PubMed  Google Scholar 

  • Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endoc Relat Cancer 8:97–114

    CAS  Google Scholar 

  • Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, Thaler HT, Muller WJ, Du B, Brown AM, Dannenberg AJ (2002) Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 62:5405–5407

    CAS  PubMed  Google Scholar 

  • Hwang D, Scollard D, Byrne J, Levine E (1998) Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 90:455–460

    Google Scholar 

  • Kargman SL, O`Neill GP, Vickers PJ, Evans JF, Mancini JA, Jothy S (1995) Expression of prostaglandin G/H synthase-1 and –2 protein in human colon cancer. Cancer Res 55:2556–2559

    CAS  PubMed  Google Scholar 

  • Khuder SA, Mutgi AB (2001) Breast cancer and NSAID use: a meta-analysis. Br J Cancer 84:1188–1192

    Article  CAS  PubMed  Google Scholar 

  • Kirkpatrick K, Ogunkolade W, Elkak A, Bustin S, Jenkins P, Ghilchik M, Mokbel K (2002) The mRNA expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in human breast cancer. Curr Med Res Opin 18:237–41

    Article  CAS  PubMed  Google Scholar 

  • Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Milhatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847

    CAS  PubMed  Google Scholar 

  • Kundu N, Fulton AM (2002) Selective cyclooxygenase (COX)-1 or COX-2 Inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 62:2343–2346

    CAS  PubMed  Google Scholar 

  • Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, Kim HS, Nam DK, Lee KB, Kim HC (2000) Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. Clin Cancer Res 6:519–525

    CAS  PubMed  Google Scholar 

  • Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, Haudenschild C, Lane TF, Hla T (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569

    Article  CAS  PubMed  Google Scholar 

  • Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Slikowski MX, DuBois RN (2001) Targeting cyclooxygenase-2 and her-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterol 120:1713–1719

    CAS  Google Scholar 

  • Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woernerer BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    CAS  PubMed  Google Scholar 

  • Paganini-Hill A, Chao A, Ross RK, Henderson BE (1989) Aspirin use and chronic diseases: a cohort study of the elderly. Br Med J 299:1247–1250

    CAS  Google Scholar 

  • Poremba C, Bocker W, Willenbring H, Schafer KL, Otterbach F, Burger H, Diallo R, Dockhorn-Dworniczak B (1998) Telomerase activity in human proliferative breast lesions. Int J Oncol 12:641–648

    CAS  PubMed  Google Scholar 

  • Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, Seibert K, Rao CV (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60:293–297

    CAS  PubMed  Google Scholar 

  • Reiner A, Neumeister B, Spona J, Reiner G, Schemper M, Jakesz R (1990) Immunocytochemical localization of estrogen and progesterone receptor and prognosis in human primary breast cancer. Cancer Res 50:1057–1061

    Google Scholar 

  • Ristimäki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632–635

    PubMed  Google Scholar 

  • Rolland PH, Martin PM, Jacquemier J, Rolland AM, Toga M (1980) Prostaglandin in human breast cancer: evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells. J Natl Cancer Inst 64:1061–1070

    CAS  PubMed  Google Scholar 

  • Sharpe CR, Collet JP, McNutt M, Belzile E, Boivin JF, Hanley JA (2000) Nested case-control study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage. Br J Cancer 83:112–120

    Article  CAS  PubMed  Google Scholar 

  • Shirahama T (2000) Cyclooxygenase-2 expression is up-regulated in transitional cell carcinoma and its preneoplastic lesions in the human urinary bladder. Clin Cancer Res 6:2424–2430

    CAS  PubMed  Google Scholar 

  • Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT (2000) COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89:2637–2645

    Article  CAS  PubMed  Google Scholar 

  • Subbaramaiah K, Telang N, Bansal MB, Weksler BB, Dannenberg AJ (1997) Cyclooxygnase-2 gene expression is upregulated in transformed mammary epithelial cells. Ann NY Acad Sci 833:179–185

    CAS  PubMed  Google Scholar 

  • Tan WC, Privett OS, Goldyne ME (1974) Studies of prostaglandins in rat mammary tumors induced by 7,12-dimethyl-benz(a)anthracene. Cancer Res 34:3229–3231

    CAS  PubMed  Google Scholar 

  • Tsujii M, DuBois RN (1995) Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin-endoperoxide synthase-2. Cell 83:495–501

    Google Scholar 

  • Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, Soslow RA, Masferrer JL, Woerner BM, Koki AT, Fahey TJ 3rd (1999) Cycooxygenase-2 expression is upregulated in human pancreatic cancer. Cancer Res 59:987–990

    CAS  PubMed  Google Scholar 

  • Van Rees BP, Ristimäki A (2001) Cyclooxygenase-2 in carcinogenesis of the gastrointestinal tract. Scand J Gastroenterol 36:897–903

    Article  PubMed  Google Scholar 

  • Wiese FW, Thompson PA, Kadlubar FF (2001) Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis 21:5–10

    Article  Google Scholar 

  • Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimäki A (1998) Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58:4997–5001

    CAS  PubMed  Google Scholar 

  • Yoshimura R, Sano H, Masuda C, Kawamura M, Tsubouchi Y, Chargui J, Yoshimura N, Hla T, Wada S (2000) Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 89:589–596

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Inka Buchroth and Judith Obernüfemann for excellent technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pia Wülfing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wülfing, P., Diallo, R., Müller, C. et al. Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol 129, 375–382 (2003). https://doi.org/10.1007/s00432-003-0459-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-003-0459-1

Keywords

Navigation