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Development of a Novel Prognostic Marker to Link a Potential Tumor Suppressor Gene at Chromosome 6q to Aberrant Signal Transduction Pathway in Breast Cancer

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Final rept. 15 Jul 2004-14 Jul 2005

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This is the final report on the grant Development of a novel diagnostic marker to link a potential tumor suppressor gene at chromosome 6q to aberrant signal transduction pathway in breast cancer. The purpose of the grant proposal is to examine the hypothesis that protein phosphatase laforin is a tumor suppressor in cancers through its function as the specific phosphatase of GSK-3BETA and the loss of function of laforin causes aberrant Wnt signaling in cancer cells. We have proposed to examine whether the specific marker is present in breast cancer cells whether the unique morphological marker correlates with specific LOH in 6q24 whether there are inactivating mutations in laforin gene whether loss of laforin function in breast cancer cells causes downstream effects on BETA-catenin cytosolic and nuclear accumulation and increased cyclin D and c-myc expression in breast cancer samples. Finally, we will examine whether loss of laforin function in breast cancer cells is an independent prognostic factor. In the past funding period, we have greatly extended our work in basic research to firmly establish the role of laforin as a tumor suppressor. First, we showed that silencing the Epm2a gene which encodes laforin in the bone marrow stem cells resulted in a dramatic increase in the self-renewal of the hematopoietic stem cells in methylcellulose assay in vitro and in the vitro and in the tendency for hematological malignancy transformation in vivo. Second, we demonstrated that abnormal Wnt signaling associated with laforin down-regulation is a causal event for the malignant transformation mediated by laforin-down regulation.

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  • Medicine and Medical Research

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