ISSN 2415-3060 (print), ISSN 2522-4972 (online)
  • 8 of 46
Up
УЖМБС 2022, 7(1): 68–78
https://doi.org/10.26693/jmbs07.01.068
Experimental Medicine and Morphology

Features of the COX-2 Expression in Different Molecular Subtypes of Invasive Ductal Breast Cancer

Volos L. I. 1, Dudash A. P. 1,2
Abstract

The purpose of the study was to determine the role of COX-2 in the development and progression of molecular subtypes of invasive ductal breast cancer by comparing COX-2 expression level between different clinical and pathological prognostic parameters. Materials and methods. We studied 193 cases of invasive ductal breast cancer using comprehensive morphological, including immunohistochemical methods. General histological processing of samples was performed according to standard methods. Immunohistochemical studies for COX-2, ER, PR, c-erbB2, Ki-67 were performed according to the manufacturer's protocol with the control of samples. The grade of malignancy was determined according to the modified scheme of P. Scarff, H. Bloom and W. Richardson. COX-2 expression level was quantified using the Histoscore counting system in 86 cases. Immunoreactive index was defined as the product of positive cells and color intensity with a value from 0 to 12. The distribution of tumors with weak or strong expression of COX-2 was determined at the level of limit 6. Comparison of COX-2 expression at different clinical and pathological parameters was evaluated using the criterion Pearson χ2. For all types of analysis, differences were considered significant at p <0.05. Results and discussion. Immunohistochemical studies showed overexpression of COX-2 tumor cells in 53.49 [42.95-63.87] % of cases of invasive ductal breast cancer, mainly in premenopausal patients. Increased expression of COX-2 was determined in tumors with metastases to regional lymph nodes (53.66 66 [38.46-68.52] % - 63.64 (34.52-88.13] %), large size (73, 81 (59.63-85.82] % - 85.71 [52.74-99.97] %), running clinical stage (65.12 [54.78-74.78] %), with a low degree of differentiation G3 (80.95 [61.88-94.45] %), negative ER status and overexpression of HER-2/neu. Overexpression of COX-2 prevailed in patients under the age of 50 years (69.23 [54.04-82.54] %), in patients with triple-negative carcinoma phenotype (75.00 [54.26-91.01] %) and HER-2/neu + phenotype of invasive ductal breast cancer (73.68 [52.19-90.47] %). Conclusion. Overexpression of COX-2 has been associated with adverse prognosis factors such as young age, metastatic lymph node involvement, large tumor size, G3 poorly differentiation (high grade), negative ER status and HER-2/neu overexpression, and has been associated with an increased risk of recurrence of the disease, progression of the tumor process, increased risk of death. Overexpression of COX-2 may be a sign of an aggressive phenotype with metastatic potential, depend on hormonal status and be useful as a prognostic biomarker of invasive ductal breast cancer

Keywords: invasive ductal breast cancer, COX-2 expression, prognostic factors

Full text: PDF (Ukr) 619K

References
  1. WHO, 2021 Breast cancer now most common form of cancer: WHO taking action. Available from: https://www.who. int/news/item/03-02-2021-breast-cancer-now-most-common-form-of-cancer-who-taking-action.
  2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108. PMID: 15761078. https://doi.org/10.3322/canjclin.55.2.74
  3. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. PMID: 15894097. https://doi.org/10.1016/S0140-6736(05)66544-0
  4. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ; 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007 Jul;18(7):1133-44. Erratum in: Ann Oncol. 2007 Nov;18(11):1917. PMID: 17675394. https://doi.org/10.1093/annonc/mdm271
  5. Visscher DW, Pankratz VS, Santisteban M, Reynolds C, Ristimäki A, Vierkant RA, et al. Association Between Cyclooxygenase-2 Expression in Atypical Hyperplasia and Risk of Breast Cancer. JNCI: J National Cancer Ins. 2008;100(6):421–427. PMID: 18334709. https://doi.org/10.1093/jnci/djn036
  6. Yang WT, Lewis MT, Hess K et al. Decreased TGFbeta signaling and increased COX2 expression in high-risk women with increased mammographic breast density. Breast Cancer Res Treat. 2010 Jan;119(2):305-14. PMID: 19241157; PMCID: PMC5921048. https://doi.org/10.1007/s10549-009-0350-0
  7. Krcova Z, Ehrmann J, Krejci V, Eliopoulos A, Kolar Z. Tpl-2/Cot and COX-2 in breast cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008 Jun;152(1):21-5. PMID: 18795070. https://doi.org/10.5507/bp.2008.003
  8. Hu M, Peluffo G, Chen H, Gelman R, Schnitt S, Polyak K. Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3372-7. PMID: 19218449. PMCID: PMC2642666. https://doi.org/10.1073/pnas.0813306106
  9. Zhang XH, Huang DP, Guo GL, Chen GR, Zhang HX, Wan L, et al. Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC Cancer. 2008;8(4). PMID: 18190720. PMCID: PMC2253544. https://doi.org/10.1186/1471-2407-8-4
  10. Kulkarni S, Patil DB, Diaz LK, Wiley EL, Morrow M, Khan SA. COX-2 and PPARgamma expression are potential markers of recurrence risk in mammary duct carcinoma in-situ. BMC Cancer. 2008 Jan 31;8:36. PMID: 18237383. PMCID: PMC2254431. https://doi.org/10.1186/1471-2407-8-36
  11. WHO Classification of Tumors Editorial Board, ed. WHO classification of tumors. 5th edition. Breast tumors. Lyon: International Agency for Research on Cancer. 2019. PMID: 32056259. https://doi.org/10.1111/his.14091
  12. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19: 403-10. PMID: 1757079. https://doi.org/10.1111/j.1365-2559.1991.tb00229.x
  13. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al; Panel Members. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015 Aug;26(8):1533-46. PMID: 25939896. PMCID: PMC4511219. https://doi.org/10.1093/annonc/mdv221
  14. Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update. Arch Pathol Lab Med. 2020 May;144(5):545-563. PMID: 31928354. https://doi.org/10.5858/arpa.2019-0904-SA
  15. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;3:138–140.
  16. Feng Xu, Mengxin Li, Chao Zhang, Jianxiu Cui, Jun Liu, Jie Li, et al. Clinicopathological and prognostic significance of COX-2 immunohistochemical expression in breast cancer: a meta-analysis Oncotarget. 2017; 8:6003-6012. PMID: 27999206. PMCID: PMC5351608. https://doi.org/10.18632/oncotarget.13990
  17. Dhakal HP, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, et al. Expression of cyclooxygenase-2 in invasive breast carcinomas and its prognostic impact. Histol Histopathol. 2012 Oct;27(10):1315-25. PMID: 22936450. https://doi.org/10.14670/HH-27.1315
  18. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, Thill M. Impact of cyclooxygenase-2 in breast cancer. Anticancer Res. 2011 Dec;31(12):4359-67. PMID: 22199301
  19. 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
  20. Ristimäki 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 Feb 1;62(3):632-5. PMID: 11830510
  21. Watanabe O, Shimizu T, Imamura H, Kinoshita J, Utada Y, Okabe T, et al. Expression of cyclooxygenase-2 in malignant and benign breast tumors. Anticancer Res. 2003 Jul-Aug;23(4):3215-21. PMID: 12926055
  22. Boland GP, Butt IS, Prasad R, Knox WF, Bundred NJ. COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ. Br J Cancer. 2004;90(2):423-429. PMID: 14735188. PMCID: PMC2409574. https://doi.org/10.1038/sj.bjc.6601534
  23. Witton CJ, Hawe SJ, Cooke TG, Bartlett JM. Cyclooxygenase 2 (COX2) expression is associated with poor outcome in ER-negative, but not ER-positive, breast cancer. Histopathology. 2004 Jul;45(1):47-54. PMID: 15228443. https://doi.org/10.1111/j.1365-2559.2004.01898.x
  24. 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 Mar 15;62(6):1676-81. PMID: 11912139
  25. 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 May 24;277(21):18649-57. PMID: 11901151. https://doi.org/10.1074/jbc.M111415200
  26. Costa C, Soares R, Reis-Filho JS, Leitão 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 Jun;55(6):429-34. PMID: 12037025. PMCID: PMC1769664. https://doi.org/10.1136/jcp.55.6.429
  27. Zeeneldin AA, Mohamed AM, Abdel HA, Taha FM, Goda IA, Abodeef WT. Survival effects of cyclooxygenase-2 and 12-lipooxygenase in Egyptian women with operable breast cancer. Indian J Cancer. 2009 Jan-Mar;46(1):54-60. PMID: 19282568. https://doi.org/10.4103/0019-509x.48597
  28. Dillon MF, Stafford AT, Kelly G, Redmond AM, McIlroy M, Crotty TB, et al. Cyclooxygenase-2 predicts adverse effects of tamoxifen: a possible mechanism of role for nuclear HER2 in breast cancer patients. Endocr Relat Cancer. 2008 Sep;15(3):745-53. PMID: 18469157. https://doi.org/10.1677/ERC-08-0009
  29. Guo GL, Yang GL, Li ZY, You J, Yang K, Huang DP, et al. [The effect of cyclooxygenase-2 on lymphangiogenesis in breast cancer]. Zhonghua Wai Ke Za Zhi. 2008 Jan 15;46(2):132-5. [Chinese]. PMID: 18509974
  30. Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis G, Cohen C. COX-2 expression in invasive breast cancer: correlation with prognostic parameters and outcome. Appl Immunohistochem Mol Morphol. 2007 Sep;15(3):255-9. PMID: 17721268. https://doi.org/10.1097/01.pai.0000213130.63417.b3
  31. Zatelli MC, Luchin A, Tagliati F, Leoni S, Piccin D, Bondanelli M, et al. Cyclooxygenase-2 inhibitors prevent the development of chemoresistance phenotype in a breast cancer cell line by inhibiting glycoprotein p-170 expression. Endocr Relat Cancer. 2007 Dec;14(4):1029-38. PMID: 18045954. https://doi.org/10.1677/ERC-07-0114
  32. Singh B, Cook KR, Vincent L, Hall CS, Berry JA, Multani AS, et al. Cyclooxygenase-2 induces genomic instability, BCL2 expression, doxorubicin resistance, and altered cancer-initiating cell phenotype in MCF7 breast cancer cells. J Surg Res. 2008 Jun 15;147(2):240-6. PMID: 18498876. https://doi.org/10.1016/j.jss.2008.02.026