Biological Functions of Genes in the 70-Gene MammaPrint Tumor Expression Profile Reflect Molecular Mechanism of Tumor Metastasis.

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Abstract Background: MammaPrint has been validated as a reliable diagnostic tool to predict risk of distant metastasis in patients with breast cancer. In this study, we annotate the biological function of genes in the MammaPrint signature, and investigate cancer biology linking the molecular signature with respect to underlying molecular mechanism of tumor progression and tumor metastasis.Material and methods: Genes in the MammaPrint signature were translated into protein sequences. The subcellular localization, functional domain architecture and biological function of genes were annotated by using 7 different algorithms and 3 associated databases and were then interpreted within biological context. The tumor progression and tumor metastasis cascade was dissected into individual steps and the biological function of genes was subsequently associated with the tumor metastasis cascade.Results: We reveal sub cellular localization and functional domain architecture of the 70 genes in the MammaPrint signature. We find that these genes cover 12 diverse biological functional groups including metabolism; cell cycle and DNA replication; extracellular matrix adhesion and remodeling; growth, proliferation, transformation and cell death; general signal transduction and intracellular transport; growth factor; motility or actin filament organization; intracellular hydrolase; innate immune response; neuropeptide; predicted transmembrane protein with unknown function; and predicted transcriptional control or DNA binding proteins. We and demonstrate the involvement of these 70 genes in all individual steps of tumor progression and tumor metastatic cascade at both primary tumor site and metastasis site. In addition, we show that within these 70 genes, 15 genes are well known to be involved in the early embryonic development, 2 genes are known as development related transcription factors, and 3 genes (TGFB3, FGF18, WISP1) represent well characterized important epithelial-mesenchymal transition mediating TGF-β, FGF and Wnt family proteins. This is consistent with a biological model wherein tumor cells at the primary tumor site acquire metastatic ability through similar behaviors of epithelial-mesenchymal transition by turning on/off some of the same transcription factors that are used in the early embryonic development.Discussion: Our results show that genes in the MammaPrint profile cover all tumor progression and metastasis related biological processes. This finding establishes a comprehensive link between molecular signature and the underlying molecular mechanisms of tumor metastasis and explains the mechanism by which the 70-gene MammaPrint profile is predictive for the risk of distant metastasis. Further, our results support the hypothesis that the epithelial-mesenchymal transition phenomenon is a key step to conferring tumor cells with metastatic ability. Understanding underlying molecular mechanism of cancer biology reflected by the MammaPrint signature greatly improves the opportunity of applying this gene signature in clinic. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6146.