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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 PARs in ER-positive and ER-negative subgroups.Prognosis in relation to PAR-1 and PAR-2 status in patients with (a) ER-positive and (b) ER-negative tumors.
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pone.0134932.g003: One minus distant disease-free survival (DDFS) stratified by PARs in ER-positive and ER-negative subgroups.Prognosis in relation to PAR-1 and PAR-2 status in patients with (a) ER-positive and (b) ER-negative tumors.

Mentions: Previous experimental studies have established that PAR-1 and PAR-2 may heterodimerize, and co-signal during breast tumor development [13–17]. These findings, together with our above findings suggesting differential prognostic effects of PAR-1 and PAR-2 depending on ER status, motivated further analyses of potential interactions between these three factors. A Cox-model for DDFS with the three main effects for ER, PAR-1 and PAR-2, the three two-way interaction terms ER*PAR-1, ER*PAR-2 and PAR-1*PAR-2, and finally a term ER*PAR-1*PAR-2 for the three-way interaction, suggested a three-way interaction, which was almost significant (P = 0.070). To illustrate this interaction effect, prognosis in subgroups defined by PAR-1 and PAR-2 was studied separately for patients with ER-positive and ER-negative tumors (Fig 3). The HR for PAR-2 high vs. PAR-2 low in the PAR-1 high subgroup was 1.9 (95% CI: 0.31–11; P = 0.5) compared to HR = 12 (95% CI: 2.7–57; P = 0.001) in the PAR-1 low group. The DDFS in ER-positive/PAR-2 high/PAR-1 low and ER-positive/PAR-2 high/PAR-1 high was 62% and 90%, respectively (Fig 3A). The HR for PAR-1 high vs. PAR-1 low in the PAR-2 high subgroup was 4.2 (95% CI: 0.91–19; P = 0.065) compared to HR = 1.4 (95% CI: 0.28–6.9; P = 0.7) in the PAR-2 low group. The DDFS in ER-negative/PAR-1 high/PAR-2 low and ER-negative/PAR-1 high/PAR-2 high was 75% and 64%, respectively (Fig 3B). Although these subgroup analyses were clearly limited by reduction of sample size and should be interpreted with caution, the prognostic effect of PAR-2 in ER-positive patients appeared to be attenuated by concomitant high PAR-1 expression. On the contrary, the effect of PAR-1 in ER-negative tumors may be reinforced by concomitant high PAR-2 expression.


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 PARs in ER-positive and ER-negative subgroups.Prognosis in relation to PAR-1 and PAR-2 status in patients with (a) ER-positive and (b) ER-negative tumors.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134932.g003: One minus distant disease-free survival (DDFS) stratified by PARs in ER-positive and ER-negative subgroups.Prognosis in relation to PAR-1 and PAR-2 status in patients with (a) ER-positive and (b) ER-negative tumors.
Mentions: Previous experimental studies have established that PAR-1 and PAR-2 may heterodimerize, and co-signal during breast tumor development [13–17]. These findings, together with our above findings suggesting differential prognostic effects of PAR-1 and PAR-2 depending on ER status, motivated further analyses of potential interactions between these three factors. A Cox-model for DDFS with the three main effects for ER, PAR-1 and PAR-2, the three two-way interaction terms ER*PAR-1, ER*PAR-2 and PAR-1*PAR-2, and finally a term ER*PAR-1*PAR-2 for the three-way interaction, suggested a three-way interaction, which was almost significant (P = 0.070). To illustrate this interaction effect, prognosis in subgroups defined by PAR-1 and PAR-2 was studied separately for patients with ER-positive and ER-negative tumors (Fig 3). The HR for PAR-2 high vs. PAR-2 low in the PAR-1 high subgroup was 1.9 (95% CI: 0.31–11; P = 0.5) compared to HR = 12 (95% CI: 2.7–57; P = 0.001) in the PAR-1 low group. The DDFS in ER-positive/PAR-2 high/PAR-1 low and ER-positive/PAR-2 high/PAR-1 high was 62% and 90%, respectively (Fig 3A). The HR for PAR-1 high vs. PAR-1 low in the PAR-2 high subgroup was 4.2 (95% CI: 0.91–19; P = 0.065) compared to HR = 1.4 (95% CI: 0.28–6.9; P = 0.7) in the PAR-2 low group. The DDFS in ER-negative/PAR-1 high/PAR-2 low and ER-negative/PAR-1 high/PAR-2 high was 75% and 64%, respectively (Fig 3B). Although these subgroup analyses were clearly limited by reduction of sample size and should be interpreted with caution, the prognostic effect of PAR-2 in ER-positive patients appeared to be attenuated by concomitant high PAR-1 expression. On the contrary, the effect of PAR-1 in ER-negative tumors may be reinforced by concomitant high PAR-2 expression.

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