Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the highaffinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients. (Cancer Res 2006; 66(12): 6243-9)
The synucleins are a small, soluble, highly conserved group of neuronal proteins that have been implicated in both neurodegenerative diseases and cancer. The synuclein family consists of alpha-, beta-, and gamma-synucleins (gamma-syn). They are a natively unfolded group of proteins that share sequence homologies and structural properties. So far, the biological functions of the synucleins are still unclear, but their involvement in neurodegenerative diseases and cancer may provide insights into the pathological processes that result from these two groups of debilitating diseases, and present the possibility to use them as potential targets for early diagnosis and treatment. Recently, elevated levels of gamma-syn proteins have been detected in various types of cancer, especially in advanced stages of the disease. Furthermore, studies to date indicate that overexpression of gamma-syn compromises normal mitotic checkpoint controls, resulting in multinucleation as well as faster cell growth. Gamma-syn has also been shown to promote invasion and metastasis in in vitro assays as well as in animal models. Overexpression of gamma-syn also interferes with drug-induced apoptotic responses. These observations raise questions about the involvement of gamma-syn in the process of tumorigenesis and metastasis, and efforts have already been made to use gamma-syn as a marker for assessing breast cancer progression. This review will discuss the involvement of gamma-syn in cancer progression, metastasis and its potential as a marker.
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