Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer

Abstract

COX-2 regulates tumour growth, invasion and metastasis in breast cancer. This study investigated the association between COX-2 expression in human breast cancer versus the expression of ER, PR, HER-2/neu, as well as its association with other established prognostic indicators like age, menopausal status, tumour size, lymph nodal status, stage, grade, NPI and histological subtype, and aims to validate the role of overexpression of COX-2 as a prognostic marker in patients with breast cancer in Indian subcontinent. In this hospital based study of 123 breast cancer patients (Group-A) and 76 female patients with benign breast disease (Group-B) attending a Comprehensive Breast Clinic at a reputed institute in Eastern India, COX-2 protein expression was measured from breast tissue using the Western Blot Technique. COX-2 mRNA expression was measured by RT-PCR Technique. ER, PR and HER-2/neu status was measured by immunohistochemistry methods. COX-2 was not expressed in the control group. The proportion of COX-2 positive tumours was significantly higher in patients of age >50 years [52(91.2 %), p < 0.01], postmenopausal status [64(90.1 %), p < 0.01], advanced stage of disease (p < 0.01), higher grade (p < 0.01), larger tumors (p < 0.01), metastatic lymph nodes (p < 0.01) and NPI ≥ 5.4 (p < 0.01). COX-2 expression was seen in ER-negative [66(95.7 %), p < 0.01], PR-negative [76(92.7 %), p < 0.01], and HER-2/neu positive tumours [29(100.0 %), p < 0.01]. Risk of COX-2 positivity was found to be 2.74 times more for postmenopausal status, 6.90 times more for large size tumours (≥ 2.5), 34.37 times more for node positive tumours, 9.26 times more with ER negative patients and 5.88 times more for PR negative patients. COX-2 expression is associated with established indicators of poor prognosis such as postmenopausal status, age >50 year, advanced stage of disease, large tumour size, higher grade, lymph node metastasis, NPI ≥ 5.4, ER negativity, PR negativity and HER-2/neu positivity. Thus, COX-2 expression implies aggressive tumour biology, and may play an important role as a prognostic marker.

Keywords: Breast cancer; COX-2; Immunohistochemistry (IHC); Nottingham Prognostic Index (NPI); Prognostic marker.

Fig. 1

a. represents that COX-2 was expressed more in ER negative tumours as compared to ER positive tumours as determined by western blot method. b. represents that COX-2 was expressed more in ER negative tumours as compared to ER positive tumours as determined by RT-PCR technique

Fig. 2

a. represents that COX-2 was expressed more in HER-2/neu positive tumours as compared to HER-2/neu negative tumour as determined by western blot method. b. represents that COX-2 was expressed more in HER-2/neu positive tumours as compared to HER-2/neu negative tumour as determined by RT-PCR technique

Fig. 3

A model for ER, COX-2 and HER-2/neu interactions. ER regulates gene expression through protein-protein interactions with other transcription factors, e.g. activator protein1 (AP-1) and then COX-2 expressed through Ras, Raf, MAPK pathway. Our study demonstrates that COX-2 can stimulate HER-2/neu expression via EGFR through the major role of PGE-2