Cancer du sein et micro-environnement tumoral: rôle de la protéase ...

INTRODUCTIONLysosomal aspartic protease cathepsin-D (cath-D) is overexpressed and highlysecreted by human epithelial breast cancer cells (1-4). Its overexpression in breastcancer is correlated with poor prognosis (5-7). Cath-D is synthesized as a 52-kDa,catalytically-inactive precursor. It is present in endosomes as an active 48-kDa,single-chain intermediate that is subsequently converted in the lysosomes into thefully active mature protease, composed of a 34-kDa heavy chain, and a 14-kDa lightchain. The 52-kDa pro-cath-D hypersecreted by breast cancer cells into theextracellular environment is endocytosed by both cancer cells and fibroblasts (1, 8,9). While cath-D endocytosis is mainly performed by the mannose-6-phosphatereceptors (M6PR), the existence of alternative cath-D receptors has been postulated(10, 11). Cath-D affects both cancer cells and stromal cells in the tumor microenvironmentby increasing cell proliferation, metastasis, angiogenesis and fibroblastoutgrowth (1, 12-16). We previously observed that a mutated catalytically-inactiveversion of cath-D (D231N) remains mitogenic for tumor cells and fibroblasts (12, 14,15), suggesting that cath-D acts as an extracellular messenger that interacts eitherdirectly or indirectly with an as-yet unidentified cell surface receptor.Here, we identify the fibroblast receptor that mediates the cath-D-inducedparacrine fibroblast outgrowth, LDL receptor-related protein-1 (LRP1). LRP1 iscomposed of a 515-kDa extracellular a chain, and an 85-kDa b chain (17, 18). Theb chain contains an extracellular domain, a trans-membrane region, and acytoplasmic tail. The extracellular a chain contains binding-sites for many structurallyunrelated ligands, including lipoprotein particles, proteases and protease-inhibitorcomplexes. At present, the ligands of the extracellular domain of the LRP1b chain are3