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    Research Grants Awarded

    A Multidisciplinary Approach to Uncover FoxO3a Targets Contributing to Apoptotic Signaling in Breast Cancer

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Our laboratory has discovered that activation of the glucocorticoid receptor (GR) inhibits breast epithelial and cancer cells from undergoing programmed cell death. This GR-mediated model of anti-apoptotic signaling has allowed us to uncover an important cell survival pathway that requires the transcriptional induction of serum and glucocorticoid-inducible kinase-1 ( SGK-1 ). Our data demonstrate that SGK-1 induction is associated with FoxO3a phosphorylation and its subsequent inactivation, which in turn contributes to GR-mediated breast cancer cell survival. Identifying novel pro-apoptotic FoxO3a target genes may be useful for developing targeted therapies to treat breast cancer. This project will test the hypothesis that novel pro-apoptotic target genes of FoxO3a can be efficiently identified using a multidisciplinary approach that combines bioinformatics, molecular biology, and pathology. Specific Aim 1 will use a novel bioinformatic approach to identify FoxO3a target genes from time course microarray data following GR activation . In this aim, we will first use promoter element analysis to identify GR-downregulated genes that have Foxo3a binding sequences. We will then select a subset of these genes whose time course expression exhibits an inverse pattern in relation to that of SGK-1 as final candidate target genes of FoxO3a. Specific Aim 2 will test whether putative FoxO3a target genes identified in Aim 1 are valid, and examine their functional roles in GR-mediated cell survival signaling. Specific Aim 3 will examine whether FoxO3a target genes validated in Aim 2 have differential protein expression in primary human breast cancer tumors compared with matched normal breast tissues. Specific Aim 4 will test the effect of over-expression of the pro-apoptotic FoxO3a target genes independently of GR activation on the chemotherapy response of human breast cancer xenografts in a SCID mouse model. Identification of novel FoxO3a target genes may be useful for developing new therapies to treat breast cancer. To address this need, we propose a multidisciplinary approach that combines three powerful disciplines –bioinformatics, molecular biology and pathology- to discover novel pro-apoptotic FoxO3a target genes and to test their functional roles in breast cancer.

    Lay Abstract:
    Breast cancer is a leading cause of death in women. In order to cure breast cancer, we need to find out why breast cancer cells keep growing instead of self-destructing. Our laboratory has found that when we treat breast cancer cells with stress hormones such as dexamethasone (dex), the effectiveness of chemotherapy is significantly diminished. We have found that several genes that are turned on by dex in breast cancer cells are associated with inhibiting chemotherapy effectiveness. One of these genes is called serum and glucocorticoid-inducible kinase-1 (SGK-1). We have shown that SGK-1 causes breast cancer cells to survive by in turn inactivating a cell death protein called FoxO3a. However, we do not know exactly how inactivation of FoxO3a causes a breast cancer cell to survive. If we can identify the genes targeted by the action of FoxO3a, we will be able to find out how the stress hormones cause breast cancer cells to resist cell death. To identify these important FoxO3a target genes, we have developed a powerful computational method that can systematically analyze the expression of thousands of genes in breast cancer cells, which have been treated with dex and subsequently identify FoxO3a-regulated genes. This task can not be achieved efficiently through the use of traditional biological techniques alone. Once target genes are identified using this computational approach, we will determine whether increased expression of putative FoxO3a target genes can indeed cause breast cancer cells to die using traditional molecular biology techniques and animal models. Increasing the expression of FoxO3a target genes is expected to improve the efficiency of current therapies used to treat breast cancer by causing tumor cell death. The results from the research proposed in this postdoctoral fellowship application are expected to identify these genes and therefore to one day benefit breast cancer patients.