Abstract 4052: Analysis of the matrix metalloproteinase family reveals MMP8 is often mutated in melanoma

Abstract

Abstract Matrix Metalloproteinases (MMPs) have long been associated with multiple biological processes and a variety of pathological conditions, including cancer because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. We performed a mutational analysis of the Matrix Metalloproteinase gene family in human melanoma and identified 28 somatic mutations in eight MMPs, affecting 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8, reduced MMP-8 enzyme activity. Expression of wild-type but not mutant MMP-8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wild-type MMP-8 has the ability to inhibit melanoma progression. Our findings emphasize the need to test the role of each MMP in an individual manner and to precisely define its functional role in cancer. This may allow the development of individualized therapy based on the mutant MMP present in specific tumors. To extend our knowledge of fundamental roles of proteases in cancer progression, we will compliment the studies by performing a systematic sequence analysis of all ADAMs (A Disintegrin And Metallproteinase) and the related ADAMTS family. Similar to MMPs, ADAM/ADAMTS belong to a super family of zinc-based proteinases, the metzincins. Many members of the ADAM/ADAMTS family have been associated with tumorigenesis and tumor progression. Therefore, our comprehensive genetic studies will provide insight into melanoma pathogenesis. In-depth illustrations of the biochemical and biological effects of the mutated genes will permit the design of personalized treatments for melanoma patients. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4052.