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Unleashing the therapeutic potential of maspin Between 1970 and 1994, well over 1 million people died as a consequence of breast cancer in the US alone. Consequently the search for new targets remains intense. New targets should be able to slow the growth and spread of tumors and particularly exciting in this respect has been the discovery in 1994 and the subsequent development of maspin. The gene expressing this member of the serpin family of protease inhibitors was identified by differential display as a tumor suppressor gene. Maspin mRNA is expressed in normal mammary epithelial cells, but not in most mammary tumor cell lines examined. Transfection of mammary carcinoma cells with the maspin gene, or the use of recombinant maspin, reduced their ability to induce tumors and metastasize in nude mice. This appears to be related to reduced angiogenesis and invasive activity and, possibly enhanced apoptosis. Reduced maspin levels in cancer appears to be due to reduced transcription. In normal cells, the SERPINB5 (the maspin gene) promoter is unmethylated and the promoter region has acetylated histones and an accessible chromatin structure. By contrast, normal cells that do not express SERPINB5 have a completely methylated SERPINB5 promoter with hypoacetylated histones and an inaccessible chromatin structure. This would suggest that therapeutic agents able to inhibit SERPINB5 methylation or deacetylation represent an excellent approach to the treatment of breast cancer. This concept has been proved in part by University of Kiel researchers. This group has shown that the treatment of a series of maspin-negative breast cancer cell lines with the demethylating agent 5-aza-2(') deoxycytidine, the histone deacetylase inhibitors, trichostatin A or a combination of both, led to the re-expression of maspin. The therapeutic use of histone deacetylase inhibitors represents a vast yet under-exploited field of oncology and as a result LeadDiscovery recently published a state of the art review of this area, including advice on how to harness this field to develop targeted treatments of cancer. Companies with an interest in exploiting maspin, or indeed histone deacetylase inhibitors in general may find this review of use. Entry date September, 2002 Adapted from Maass et al, Biochem Biophys Res Commun 2002 Sep 13;297(1):125
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