Cyclooxygenase-2 Expression in Invasive Breast Carcinomas of No Special Type and Correlation with Pathological Profiles Suggest a Role in Tumorigenesis Rather than Cancer Progression

  • Published : 2015.03.09


Background: COX-2 has been shown to play an important role in the development of breast cancer and increased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigate the relationship between COX-2 immunohistochemical expression and known predictive and prognostic factors in breast cancer in a routine diagnostic histopathology setting. Materials and Methods: Formalin-fixed paraffin-embedded tumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed between January 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained with COX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2-neu overexpression, histological grade, tumour size and lymph node status. Results: COX-2 was overexpressed in 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours. There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had the lowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed. There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and 66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller size tumours was observed but this did not reach statistical significance. There was no relationship between COX-2 expression and lymph node status. Conclusions: This study did not support the generally held notion that COX-2 overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies with outcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whether COX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In either setting, the pathological assessment for COX-2 overexpression in breast cancers would have an important role in the selection of cancer patients for personalized therapy with COX-2 inhibitors.


Grant : Enhancing personalized medicine through pathological profiling of cancer

Supported by : FRGS IPTA


  1. Azrad M, Demark-Wahnefried W (2014). The association between adiposity and breast cancer recurrence and survival: A review of the recent literature. Curr Nutr Rep, 1, 9-15.
  2. Baumgarten SC, Frasor J (2012). Minireview: inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol, 26, 360-71.
  3. Brodie AM, Lu Q, Long BJ, et al (2001). Aromatase and COX-2 expression in human breast cancers. J Steroid Biochem Mol Biol, 79, 41-7
  4. Cho MH, Yoon JH, Jaegal YJ, et al (2006). Expression of cyclooxygenase-2 in breast carcinogenesis and its relation to HER-2/neu and p53 protein expression in invasive ductal carcinoma. Breast, 15, 390-8.
  5. Ciris IM, Bozkurt KK, Baspinar S, Kapucuoglu FN (2011). Immunohistochemical Cox-2 overexpression correlates with Her-2/Neu overexpression in invasive breast carcinomas: a pilot study. Pathol Res Pract, 207, 182-7
  6. Dhakal HP, Naume B, Synnestvedt M, et al (2012). Expression of cyclooxygenase-2 in invasive breast carcinomas and its prognostic impact. Histol Histopathol, 27, 1315-25.
  7. Dalamaga M (2013). Obesity, insulin resistance, adipocytokines and breast cancer: new biomarkers and attractive therapeutic targets. World J Exp Med, 3, 34-42
  8. De Moraes E, Dar NA, de Moura Gallo CV, Hainaut P (2007). Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis. Int J Cancer, 121, 929-37.
  9. Dean SJ, Perks CM, Holly JM, et al (2014). Loss of PTEN expression is associated with IGFBP2 expression, younger age and late stage in triple-negative breast cancer. Am J Clin Pathol, 141, 323-33
  10. Nam E, Lee SN, Im SA, et al (2005). Expression of cyclooxygenase-2 in human breast cancer: relationship with HER-2/neu and other clinicopathological prognostic factors. Cancer Res Treat, 37, 165-70.
  11. Furstenberger G, Krieg P, Muller-Decker K, Habenicht AJ (2006). What are cyclooxygenases and lipoxygenases doing in the driver's seat of carcinogenesis? Int J Cancer, 119, 2247-54.
  12. Glover JA, Hughes CM, Cantwell MM, Murray LJ (2011). A systematic review to establish the frequency of cyclooxygenase-2 expression in normal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma of the breast and invasive breast cancer. Br J Cancer, 105, 13-7.
  13. Hammond MEH, Hayes DF, Dowsett M, et al (2010). American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med, 134, 907-22.
  14. Harris RE (2009). Cyclooxygenase-2 (COX-2) blockade in the chemoprevention of cancers of the colon, breast, prostate and lung. Inflammopharmacology, 17, 55-67.
  15. Holmes MD, Chen WY, Li L, et al (2010). Aspirin intake and survival after breast cancer. J Clin Oncol, 28, 1467-72.
  16. Lakhani S, Ellis I, Schnitt S, et al (2012). WHO Classification of Tumours of the Breast, 4th ed. Lyon, IARC Press.
  17. Lee JA, Bae JW, Woo SU, Kim H, Kim CH (2010). Correlation between COX-2 expression and hormone receptors in invasive ductal breast cancer. J Korean Surg Soc. 78, 140-8
  18. Lu S, Yu G, Zhu Y, Archer MC (2005). Cyclooxygenase-2 overexpression in MCF-10F human breast epithelial cells inhibits proliferation, apoptosis and differentiation and causes partial transformation. Int J Cancer, 116, 847-52.
  19. McPherson K, Steel CM, Dixon JM (2000). ABC of breast diseases. Breast cancer-epidemiology, risk factors and genetics. BMJ, 321, 624-8
  20. Markkula1 A, Simonsson M, Rosendahl AH (2014). Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients. Int J Cancer, 135, 1898-910.
  21. Miglietta A, Toselli M, Ravarino N, et al (2010). COX-2 expression in human breast carcinomas: correlation with clinicopathological features and prognostic molecular markers. Expert Opin Ther Targets, 14, 655-64.
  22. Mohammad AM, Abdel HA, Abdel W, et al (2006). Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer, 43,163-8.
  23. Park K, Han S, Shin E, Kim HJ, Kim JY (2006). Cox-2 expression on tissue microarray of breast cancer. Eur J Surg Oncol, 32, 1093-6
  24. Perrone G, Santini D, Vincenzi B, et al (2005). COX-2 expression in DCIS: correlation with VEGF, HER-2/neu, prognostic molecular markers and clinicopathological features. Histopathology, 46, 561-8.
  25. Ristimaki A, Sivula A, Lundin J, et al (2002). Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res, 62, 632-5.
  26. Schmitz KJ, Callies R, Wohlschlaeger J, et al (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, 685-91.
  27. Schnitt SJ (2010). Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Modern Pathology, 23, 60-4
  28. Shalaby MA, Nounou HA, Alanazi MS, et al (2014). Associations between single nucleotide polymorphisms of COX-2 and MMP-2 genes and colorectal cancer susceptibility in the Saudi population. Asian Pac J Cancer Prev, 15, 4989-94.
  29. Sinn H-P, Kreipe H (2013). A brief overview of the who classification of breast tumors, 4th edition, focusing on issues and updates from the 3rd edition. Breast Care, 8, 149-54.
  30. Sharpe CR, Collet JP, McNutt M, et al (2000). Nested case-control study of the effects of non-steroidal antiinflammatory drugs on breast cancer risk and stage. Br J Cancer, 83, 112-20.
  31. Simpson ER, Brown KA (2013). Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol, 51, 51-9.
  32. Soslow RA, Dannenberg AJ, Rush D, et al (2000). COX-2 is expressed in human pulmonary, colonic and mammary tumors. Cancer, 89, 2637-45.<2637::AID-CNCR17>3.0.CO;2-B
  33. Tarone RE, Chu KC (2002). The greater impact of menopause on ER-than ER+breast cancer incidence: a possible explanation (United States). Cancer Causes Control, 13, 7-14.
  34. Witton CJ, Hawe SJ, Cooke TG, Bartlett JM (2004). Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology, 45, 47-54.
  35. Wolff AC, Hammond ME, Schwartz JN, et al (2007). American Society of clinical oncology/college of American pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med, 131, 18-43.
  36. Wulfing P, Diallo R, Muller C, et al (2003). Analysis of cyclooxygenase-2 expression in human breast cancer: high throughput tissue microarray analysis. J Cancer Res Clin Oncol, 129, 375-82.
  37. Yersal O, Barutca S (2014). Biological subtypes of breast cancer: prognostic and therapeutic implications. World J Clin Oncol, 5, 412-24
  38. Youlden DR, Cramb SM, Dunn NA, et al (2012). The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol, 36, 237-48.
  39. Zainal Ariffin O, Nor Saleha IT (2011). National cancer registry report 2007. In O Zainal Ariffin and I. T. N. Saleha (Eds.). Kuala Lumpur: Ministry of Health.

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