Abstract
COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC.COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC. The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype.COX-2 mRNA was overexpressed in 2% of BC and significantly associated with TN subtype. Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations. TCGA validation cohort confirmed that patients with low COX-2 expression PIK3CA wt tumors had the worse disease-free survival (DFS) compared to all other subgroups. Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only. Celecoxib antitumoral activity involved S6 ribosomal protein and AKT phosphorylation.Low expression of COX-2 has a significant negative impact on the MFS/DFS of BC patients. Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX. These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy.
Highlights
The cyclooxygenase-2 (COX-2) known as the prostaglandin-endoperoxide synthase-2 (PTGS-2) is an inducible enzyme involved in inflammatory and oncogenic processes
We first quantified the expression level of COX-2 transcript by quantitative RT-PCR in a cohort of 446 breast cancer (BC) samples composed of 68 HR-ERBB2, 42 HRERBB2+, 285 HR+ERBB2- and 51 HR+ERBB2+ cases
In patientderived xenografts (PDX), the strongest expression levels of COX-2 were found in triple-negative compared to luminal (p=0.0006) and ERBB2 positive subtypes (p=ns) (Supplementary Figure S1B)
Summary
The cyclooxygenase-2 (COX-2) known as the prostaglandin-endoperoxide synthase-2 (PTGS-2) is an inducible enzyme involved in inflammatory and oncogenic processes. It is responsible for the synthesis of prostaglandins from arachidonic acid [1] and is reported to induce the expression of aromatase in breast tissue [2, 3]. No clear conclusion on COX-2 expression levels in normal breast epithelium was reported in the latter study [4]. COX-2 expression in the normal breast epithelium fluctuated (more than 40-fold) www.impactjournals.com/oncotarget among women and was correlated with COX-2 expression levels in DCIS and invasive cancer, independently of known prognostic features. This negative prognostic impact may be counterbalanced by hormonal treatment [6,7,8,9,10]
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