COX-2 expression is associated with an aggressive phenotype in ductal carcinoma in situ

Abstract

Cyclooxygenase type-2 (COX-2) is overexpressed in malignant tumours including breast cancers, though the mechanism of upregulation is unclear. This study aimed to determine COX-2 expression in ductal carcinoma in situ (DCIS) in comparison to invasive breast cancer (IBC) and normal breast, and also to investigate the relationship of COX-2 expression with HER-2 expression, oestrogen receptor (ER), tumour grade and cellular proliferation (Ki67) in DCIS. Cyclooxygenase type-2, HER-2, ER and Ki67 expression were determined by immunohistochemistry on paraffin tissue sections of DCIS (n=187), IBC (n=65) and normal breast reduction tissue (n=60). Cyclooxygenase type-2 expression in DCIS (67%, P<0.001) and IBC (63%, P<0.001) was significantly greater than in normal breast (23%). There was no difference in COX-2 expression level between DCIS and IBC (P=0.87) or between normal breast from reduction mammoplasty tissue and normal breast ducts around DCIS (22%, P=0.29). In DCIS, COX-2 expression was associated with higher cellular proliferation rates (P<0.0001), nuclear grade (P=0.003), with ER negativity (P=0.003) and with HER-2 positivity (P<0.0001). Cyclooxygenase type-2 expression is upregulated in in situ breast cancer and is associated with surrogate markers of an aggressive DCIS phenotype including nonoestrogen-regulated signalling pathways. Cyclooxygenase type-2 inhibition may potentially prevent the development of ER-positive and ER-negative breast cancers.

Figure 1

COX-2 expression in normal and neoplastic breast tissue. For each tissue, the thick black horizontal bars represent the median COX-2 score, the boxes represent the interquartile range and the T-bars the full range. The median COX-2 expression in neoplastic DCIS and invasive cancer epithelium are significantly greater than in normal breast ducts (P<0.0001), although there was no difference between DCIS and invasive cancer in median expression (P=0.59).

Figure 2

Association between COX-2 expression score and cell proliferation (Ki67-labelling index) for DCIS, IBC and normal breast. For DCIS and IBC, individual ki67 scores are separated by nuclear grade. The thick black horizontal lines represent the median Ki67 score for each COX-2 score (0–3) for each tissue. For each tissue type, there is a significant increase in Ki67 with increasing COX-2 score. In DCIS and IBC, the median Ki67 increases with increasing nuclear grade, although this is only significant for DCIS (P=0.003).

Figure 3

(A) DCIS showing minimal COX-2 expression with scanty brown cytoplasmic immunostaining (score 1+, classified as COX-2 negative), (B) moderate COX-2 staining with approximately 5060% of cells strongly stained (score 2+, classified as COX-2 positive), (C) High COX-2 expression in cribriform DCIS with 100% of cells intensely stained (score 3+, classified as COX-2 positive), (D) HER-2 staining in DCIS: note the strong membranous staining (score 3+, classified HER-2 positive).