Relationships of protein biomarkers of the urokinase plasminogen activator system with expression of their cognate genes in primary breast carcinomas

Abstract

Background: uPA, its receptor uPAR, and inhibitors PAI-1 and PAI-2 play key roles in membrane remodeling/invasion and in predicting response to chemotherapy. We identified novel relationships of these biomarkers with ER/PR that indicate clinical utility for assessing breast carcinoma outcomes. Methods: Retrospective studies were performed with de-identified results of (a) uPA, uPAR, and PAI-1; (b) estrogen (ER) and progestin receptor (PR); and (c) clinical outcomes. Relative expression of 22 000 genes from microarray of RNA from LCM-procured breast cancer cells was used with R Studio version 3.4.1. Results: Primary ER/PR status was related to uPA, uPAR, or PAI-1 levels. ER− or PR− cancers expressed elevated uPA, uPAR, and PAI2 mRNA compared to ER+ or PR+ cells. Inverse relationships between ER/PR protein and expression of uPA, uPAR, and PAI-2 were observed, whereas HER2 status was unrelated. qPCR analyses showed RERG and NQO-1 expressions were elevated in uPA− lesions, while CD34 and EDG-1 were elevated in uPAR− cancers. ERBB4 was overexpressed in PAI-1+ carcinomas. Cox regression analyses revealed relationships of ER/PR status and uPA system members with regard to clinical outcomes of breast cancer. Conclusions: uPA, uPAR, PAI1, or PAI2 expression was increased in either ER− or PR− cancers similar to that of protein content in ER−/PR− carcinomas, suggesting sex hormones regulate the uPA system in breast cancer. Results revealed protein content of uPA system members was related to ER/PR status of primary lesions. Use of LCM-procured carcinoma cells uncovered relationships between expression of known cancer−associated genes and protein content of uPA system members. Collectively, results indicate evaluation of ER and PR protein of primary breast cancers combined with analyses of uPA, uPAR, and PAI-1 protein content improves assessment of clinical outcomes.