Heparanase: A Critical Determinant of Breast Cancer Metastasis to Brain.

Abstract

Abstract Identification of mechanisms responsible for brain-metastatic breast cancer (BMBC) is imperative for the development of novel therapies. Heparanase (HPSE) is the only functional mammalian endoglycosidase degrading heparan sulfate (HS), the main polysaccharide component of growth factor - binding cell surface and extracellular matrix proteoglycans. HPSE relevance in cancer invasion and metastasis has been established. HPSE overexpression correlates with cancer metastasis, tumor vascularity, and the reduced post-operative survival of cancer patients, making it a promising target for anti-cancer therapeutics.Her-2 is a member of the epidermal growth factor receptor (EGFR) family; Her-2 overexpression and EGFR positivity are key characteristics of BMBC. EGFR is important for Her-2 signaling via Her-2/EGFR heterodimer formation. However, mechanisms linking Her-2 function and pathways to precise targets and BMBC onset have not been investigated.We hypothesize that Her-2/EGFR activation augments BMBC by inducing HPSE. We examined HPSE expression, intracellular trafficking, and activity in human Her-2 expressing BMBC models. We demonstrate that: 1) HPSE is expressed in human BMBC cells and expression is augmented according to their metastatic propensities (231parental > 231Br > 231Br2 > 231Br3); 2) EGF induces HPSE expression and nucleolar localization in Her-2 expressing BMBC cells in a dose- and time-dependent fashion; 3) DNA Topoisomerase I (Topo I) is a HPSE target in nucleoli; and 4) HPSE affects Topo I activity and function. Topo I is essential for transcription, and abnormal levels of the enzyme have been observed in a variety of tumors, including brain tumors.These novel findings are relevant to BMBC mechanisms. HPSE – Her-2 interactions will be elucidated to decipher how Her-2 signaling regulates HPSE functionality and mechanistic linkages between these two oncogenic proteins in BMBC cell lines and pre-clinical models. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6156.