title: uPA and PAI-1-Related Signaling Pathways Differ between Primary Breast Cancers and Lymph Node Metastases.
abstract: The supporting role of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor 1 (PAI-1) in migration and invasion is well known. In addition, both factors are key components in cancer cell-related signaling. However, little information is available for uPA and PAI-1-associated signaling pathways in primary cancers and corresponding lymph node metastases. The aim of this study was to compare the expression of uPA and PAI-1-associated signaling proteins in 52 primary breast cancers and corresponding metastases. Proteins were extracted from formalin-fixed paraffin-embedded tissue samples of the primary tumors and metastases. Protein lysates were subsequently analyzed by reverse phase protein array for the expression of members of the PI3K/AKT (FAK, GSK3-β, ILK, pGSK3-β, PI3K, and ROCK) and the MAPK pathways (pp38, pSTAT3, and p38). A solid correlation of uPA expression existed between primary tumors and metastases, whereas PAI-1 expression did not significantly correlate between them. The correlations of uPA and PAI-1 with signaling pathways found in primary tumors did not persist in metastases. Analysis of single molecules revealed that some correlated well between tumors and metastases (FAK, pGSK3-β, ILK, Met, PI3K, ROCK, uPA, p38, and pp38), whereas others did not (PAI-1 and GSK3-β). Whether the expression of a protein correlated between tumor and metastasis or not was independent of the pathway the protein is related to. These findings hint at a complete deregulation of uPA and PAI-1-related signaling in metastases, which might be the reason why uPA and PAI-1 reached clinical relevance only for lymph node-negative breast cancer tissues.
authors.affiliation: Department of Pathology, Technische Universität München, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Malinowsky
authors.forename: Claudia
authors.initials: C
authors.lastname: Wolff
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Holger
authors.initials: H
authors.lastname: Bronger
authors.forename: Heiko
authors.initials: H
authors.lastname: Mannsperger
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Korf
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Becker