Expression of Cyclooxygenase-2 in Human Breast Cancer: Relationship with HER-2/neu and other Clinicopathological Prognostic Factors

Nam, Eun-Mi;Lee, Soon-Nam;Im, Seock-Ah;Kim, Do-Yeun;Lee, Kyoung-Eun;Sung, Sun-Hee

  • Published : 20050600

Abstract

Purpose: Previous epidemiologic studies have demonstrated that nonsteroidal anti-inflammatory drugs can reduce the risk of breast cancer, and this possibly happens via cyclooxygenase (COX) inhibition. Moreover, growth factor-inducible COX-2, which is overexpressed in neoplastic tissue, is an attractive therapeutic target. Thus, we evaluated the expression of COX-2 in breast cancer tissues, and we assessed the association between COX-2 expression and HER-2/neu expression and also with several clinicopathological features. Materials and Methods: We analyzed the surgical specimens from 112 women with breast cancer who had undergone lumpectomy or mastectomy. The expressions of COX-2, HER-2/neu, MMP-2 and TIMP-2 were determined immunohistochemically. The correlations between COX-2 expression and several variables, including clinicopathological factors, HER-2/neu expression, MMP-2 expression and TIMP-2 expression were analyzed. Survival analysis was also performed with respect to COX-2 overexpression. Results: The overexpression of COX-2 protein was observed in 28.6% of the breast cancer tissues. Tumors with lymph node metastasis more frequently showed COX-2 overexpression than did those tumors without metastasis (p=0.039), and the increased COX-2 expression correlated positively with HER-2/neu overexpression (p=0.000). No significant differences were found for the MMP-2 or TIMP-2 expression rates in the COX-2 positive and negative groups. The survival analysis revealed no significant differences according to the COX-2 expression. Conclusion: This study results suggest that increased COX-2 expression is related with the progression of breast cancer, e.g., with lymph node invasion. COX-2 overexpression found to be related with HER-2/neu overexpression, but not with MMP-2 or TIMP-2 expression. These results support the potential use of selective agents that inhibit COX-2 or HER-2/neu for the management of breast cancer.

Keywords

References

  1. Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325:1593-6 https://doi.org/10.1056/NEJM199112053252301
  2. Khuder SA, Mutgi AB. Breast cancer and NSAID use: a meta-analysis. Br J Cancer. 2001;84:1188-92 https://doi.org/10.1054/bjoc.2000.1709
  3. Dempke W, Rie C, Grothey A, Schmoll HJ. Cyclooxygenase-2: a novel target for cancer chemotherapy? J Cancer Res Clin Oncol. 2001;127:411-7 https://doi.org/10.1007/s004320000225
  4. Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer. 2000;89:2637-45 https://doi.org/10.1002/1097-0142(20001215)89:12<2637::AID-CNCR17>3.0.CO;2-B
  5. Kang HJ, Gong G, Jang SJ, Jung PJ, Park CK. Expression of cyclooxygenase-2 in human breast carcinoma: relevance to tumor angiogenesis and expression of estrogen receptor. Cancer Res Treat. 2001;33:286-95 https://doi.org/10.4143/crt.2001.33.4.286
  6. Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002;62:632-5
  7. Half E, Tang XM, Gwyn K, Sahin A, Wathen K, Sinicrope FA. Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Res. 2002;62:1676-81
  8. Costa C, Soares R, Reis-Filho JS, Leitao D, Amendoeira I, Schmitt FC. Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer. J Clin Pathol. 2002;55:429-34 https://doi.org/10.1136/jcp.55.6.429
  9. Ahn JH, Kim SB, Ahn SH, Gong GY, Ahn MJ, Kang YK, et al. Clinical value of cyclooxygenase-2 expression in human breast carcinoma. Cancer Res Treat. 2004;36:192-8 https://doi.org/10.4143/crt.2004.36.3.192
  10. Liu CH, Chang SH, Narko K, Trifan OC, Wu MT, Smith E, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem. 2001;276:18563-9 https://doi.org/10.1074/jbc.M010787200
  11. Kundu N, Yang Q, Dorsey R, Fulton AM. Increased cyclooxygenase-2 (COX-2) expression and activity in a murine model of metastatic breast cancer. Int J Cancer. 2001;93:681-6 https://doi.org/10.1002/ijc.1397
  12. Harris RE, Alshafie GA, Abou-Issa H, Seibert K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res. 2000;60:2101-3
  13. Kundu N, Fulton AM. Selective cyclooxygenase (COX)-1 or COX-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res. 2002;62:2343-6
  14. Watson AJ. Chemopreventive effects of NSAIDs against colorectal cancer: regulation of apoptosis and mitosis by COX-1 and COX-2. Histol Histopathol. 1998;13:591-7
  15. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60:1306-11
  16. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA. 1997;94:3336-40 https://doi.org/10.1073/pnas.94.7.3336
  17. Takahashi Y, Kawahara F, Noguchi M, Miwa K, Sato H, Seiki M, et al. Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2. FEBS Lett. 1999;460:145-8 https://doi.org/10.1016/S0014-5793(99)01328-9
  18. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-82 https://doi.org/10.1126/science.3798106
  19. Vadlamudi R, Mandal M, Adam L, Steinbach G, Mendelson J, Kumar R. Regulation of cyclooxygenase-2 pathway by HER2 receptor. Oncogene. 1999;18:305-14 https://doi.org/10.1038/sj.onc.1202307
  20. Subbaramaiah K, Norton L, Gerald W, Dannenberg AJ. Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3. J Biol Chem. 2002;277:18649-57 https://doi.org/10.1074/jbc.M111415200
  21. Howe LR. Subbaramaiah K. Patel J. Masferrer JL, Deora A, Hudis C, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 2002;62:5405-7
  22. American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed., Philadelphia: Lippincott-Raven, 1997:171-80
  23. Elston CW, Ellis IO. Assessment of histological grade. In: Elston CW, Ellis IO, eds. The breast: Systemic pathology Vol 13. 3rd ed. Edinburgh: Churchill Livingstone, 1998:368-76
  24. Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Sliwkowski MX, et al. Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth. Gastroenterology. 2001;120:1713-9 https://doi.org/10.1053/gast.2001.24844
  25. Lebeau A, Deimling D, Kaltz C, Sendelhofert A, Iff A, Luthardt B, et al. Her-2/neu analysis in archival tissue samples of human breast cancer: comparison of immunohistochemistry and fluorescence in situ hybridization. J Clin Oncol. 2001;19:354-63 https://doi.org/10.1200/JCO.2001.19.2.354