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Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status.

Lidfeldt J, Bendahl PO, Forsare C, Malmström P, Fernö M, Belting M - PLoS ONE (2015)

Bottom Line: 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).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).HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

One minus distant disease-free survival (DDFS) stratified by ER in PAR-2 and PAR-1 sub-groups.Prognosis in relation to PAR-2 (a) and PAR-1 (b) status in patients with ER-positive and ER-negative tumors.
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pone.0134932.g002: One minus distant disease-free survival (DDFS) stratified by ER in PAR-2 and PAR-1 sub-groups.Prognosis in relation to PAR-2 (a) and PAR-1 (b) status in patients with ER-positive and ER-negative tumors.

Mentions: The prognostic value of the PAR variables was evaluated in subgroups defined by established prognostic factors (Table 4). These analyses revealed a negative effect of high PAR-2 in younger patients whose tumors were small, low grade, low Ki-67, HER-2-negative, and ER- and PR-positive. Interestingly, the most striking differential effect of high PAR-2 was found depending on ER status; the effect in the ER-positive group was HR: 5.5 (95% CI: 1.8–17, P = 0.003) compared to HR: 1.2 (95% CI: 0.4–3.2, P = 0.7) in the ER-negative group. The differential effect was found to be significant (P = 0.045) in a Cox model with a term for the interaction between the two variables and it remained significant in analysis of BCM (Table 4and S3 Fig). In ER-positive tumors, the DDFS was 96% and 78% in low- and high-PAR-2 expressing groups, respectively (Fig 2A). In multivariable analysis of DDFS, PAR-2 was an independent prognostic factor in the ER-positive group (HR: 3.9, 95% CI: 1.03–15.0, P = 0.045) when adjusting for age, tumor size, grade, Ki-67and HER-2 status.


Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status.

Lidfeldt J, Bendahl PO, Forsare C, Malmström P, Fernö M, Belting M - PLoS ONE (2015)

One minus distant disease-free survival (DDFS) stratified by ER in PAR-2 and PAR-1 sub-groups.Prognosis in relation to PAR-2 (a) and PAR-1 (b) status in patients with ER-positive and ER-negative tumors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526525&req=5

pone.0134932.g002: One minus distant disease-free survival (DDFS) stratified by ER in PAR-2 and PAR-1 sub-groups.Prognosis in relation to PAR-2 (a) and PAR-1 (b) status in patients with ER-positive and ER-negative tumors.
Mentions: The prognostic value of the PAR variables was evaluated in subgroups defined by established prognostic factors (Table 4). These analyses revealed a negative effect of high PAR-2 in younger patients whose tumors were small, low grade, low Ki-67, HER-2-negative, and ER- and PR-positive. Interestingly, the most striking differential effect of high PAR-2 was found depending on ER status; the effect in the ER-positive group was HR: 5.5 (95% CI: 1.8–17, P = 0.003) compared to HR: 1.2 (95% CI: 0.4–3.2, P = 0.7) in the ER-negative group. The differential effect was found to be significant (P = 0.045) in a Cox model with a term for the interaction between the two variables and it remained significant in analysis of BCM (Table 4and S3 Fig). In ER-positive tumors, the DDFS was 96% and 78% in low- and high-PAR-2 expressing groups, respectively (Fig 2A). In multivariable analysis of DDFS, PAR-2 was an independent prognostic factor in the ER-positive group (HR: 3.9, 95% CI: 1.03–15.0, P = 0.045) when adjusting for age, tumor size, grade, Ki-67and HER-2 status.

Bottom Line: 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).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).HR = 0.5, P = 0.19 in ER-positive; P = 0.026 for differential effect).

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus