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

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...

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Bibliographic Details
Published in:PloS one Vol. 10; no. 8; p. e0134932
Main Authors: Lidfeldt, Jon, Bendahl, Pär-Ola, Forsare, Carina, Malmström, Per, Fernö, Mårten, Belting, Mattias
Format: Journal Article
Language:English
Published: United States Public Library of Science 05.08.2015
Public Library of Science (PLoS)
Subjects:
Adult
Analysis
Breast cancer
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cancer and Oncology
Cancer och onkologi
Cancer therapies
Care and treatment
Clinical Medicine
Cohort Studies
Correlation
Development and progression
Diagnosis
Endocrinology
Female
Gene expression
Growth factors
Hazards
Humans
Immunohistochemistry - statistics & numerical data
Kaplan-Meier Estimate
Kinases
Klinisk medicin
Lymphatic system
Matrix metalloproteinase inhibitors
Medical and Health Sciences
Medical prognosis
Medicin och hälsovetenskap
Metastasis
Middle Aged
Oncology
Par-2 protein
Pathology
Patients
Prognosis
Proportional Hazards Models
Protease
Proteases
Proteinase
Proteinase-activated receptor 1
Proteins
Proteolysis
Rank tests
Receptor, PAR-1 - metabolism
Receptor, PAR-2 - metabolism
Receptors
Receptors, Estrogen - metabolism
Risk factors
Signal Transduction
Statistical models
Studies
Survival
Tissue Array Analysis - statistics & numerical data
Tumors
Sweden
ISSN:1932-6203, 1932-6203
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Summary: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.
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Conceived and designed the experiments: JL POB CF PM MF MB. Performed the experiments: JL POB CF. Analyzed the data: JL POB CF MF MB. Contributed reagents/materials/analysis tools: POB PM MF. Wrote the paper: JL POB CF PM MF MB.
Competing Interests: The authors have declared that no competing interests exist.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0134932