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

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.