title: Protease Activated Receptors 1 and 2 Correlate Differently with Breast Cancer Aggressiveness Depending on Tumor ER Status.
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.
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Jon
authors.initials: J
authors.lastname: Lidfeldt
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Forsare
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden; Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, Lund, Sweden; Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D044463:Receptor, PAR-1 / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis / Q000706:statistics & numerical data
chemical_list: D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011960:Receptors, Estrogen