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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Vydáno v:	PloS one Ročník 10; číslo 8; s. e0134932
Hlavní autoři:	Lidfeldt, Jon, Bendahl, Pär-Ola, Forsare, Carina, Malmström, Per, Fernö, Mårten, Belting, Mattias
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 05.08.2015 Public Library of Science (PLoS)
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 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