Abstract
Experimental models implicate protease activated receptors (PARs) as important sensors of the proteolytic tumor microenvironment during breast cancer development. However, the role of the major PARs, PAR-1 and PAR-2, in human breast tumors remains to be elucidated. Here, we have investigated how PAR-1 and PAR-2 protein expression correlate with established clinicopathological variables and patient outcome in a well-characterized cohort of 221 breast cancer patients. Univariable and multivariable hazard ratios (HR) were estimated by the Cox proportional hazards model, distant disease-free survival (DDFS) and overall survival by the Kaplan–Meier method, and survival in different strata was determined by the log-rank test. Associations between PARs and clinicopathological variables were analyzed using Pearson’s χ2-test. We find that PAR-2 associates with DDFS (HR = 3.1, P = 0.003), whereas no such association was found with PAR-1 (HR = 1.2, P = 0.6). Interestingly, the effect of PAR-2 was confined to the ER-positive sub-group (HR = 5.5, P = 0.003 vs. HR = 1.2 in ER-negative; P = 0.045 for differential effect), and PAR-2 was an independent prognostic factor specifically in ER-positive tumors (HR = 3.9, P = 0.045). On the contrary, PAR-1 correlated with worse prognosis specifically in the ER-negative group (HR = 2.6, P = 0.069 vs. HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect). This study provides novel insight into the respective roles of PAR-1 and PAR-2 in human breast cancer and suggests a hitherto unknown association between PARs and ER signaling that warrants further investigation.
Highlights
Breast cancer is a heterogeneous disease with a substantial variation in aggressiveness and prognosis [1]
protease activated receptors (PARs)-2 was a prognostic factor for distant disease-free survival (DDFS) (HR: 3.1, 95% CI: 1.5–6.4, P = 0.003), whereas PAR-1 showed no such correlation (HR: 1.2, 95% CI: 0.6–2.3, P = 0.6) (Table 3)
The major finding of the present study is that high PAR-2 expression strongly correlates with poor prognosis in a large patient subgroup, i.e. with luminal A like tumors [27], whereas PAR1, on the contrary, appeared to be a negative prognostic factor in the ER-negative doi:10.1371/journal.pone.0134932.g003
Summary
Breast cancer is a heterogeneous disease with a substantial variation in aggressiveness and prognosis [1]. Proteases of the tumor microenvironment have emerged as important regulators of cancer cell invasiveness and metastatic capacity through stroma remodeling and increased. Protease Activated Receptor-2 in ER-Positive Breast Cancer role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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