FGF-2-Interaktionen in Mammakarzinomen und gesundem Brustdrüsengewebe

Abstract

Purpose: FGF-2 is a mitogen for many cell types. Stimulation of breast carcinoma cell proliferation by this growth factor has been reported. FGF-2 binding to its receptor tyrosine kinases (RTK) and cellular signaling are modulated by heparan sulfate proteoglycans (HSPGs). The role of these molecules in breast carcinoma growth control is unknown. HSPG alterations in breast carcinomas compared to normal mammary gland should be investigated. Material and Methods: 30 infiltrating breast carcinomas were examined. The ability of HSPGs to promote FGF-2 signaling complex assembly was tested. A FGF-2 ligand and a soluble RTK fusion protein (FR 1-AP) were used as binding probes. HSPG expression was measured by immunohistochemical detection of syndecan-1, syndecan-4 and glypican-1. Results: Other than normal gland epithelium, carcinoma cell HSPGs show increased FGF-2 binding. HSPG/FGF-2 complexes immobilize soluble FR 1-AP fusion protein, indicating that HSPGs promote FGF-2 signaling. Surprisingly, no single HSPG core protein co-localizes with this binding activity. Syndecan-1 is uniformly present in normal gland epithelium, but heterogeneously expressed in carcinomas. Syndecan-4 is highly expressed in normal gland epithelium, but reduced or lost in most carcinomas. It is lower in infiltrating than in in situ components, if both co-exist. No dramatic changes in glypican-1 expression are observed. Loss of syndecan-4 may convey an infiltrating, migratory phenotype to the carcinoma cells. Conclusion: The increased ability of carcinoma HSPG to promote FGF-2 signaling complex assembly is likely due to structural abnormalities of HS chains rather than altered core protein expression and may contribute to accelerated proliferation.