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X-Box Binding Protein-1 in Breast Cancer

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Final rept. 1 Aug 2002-31 Jul 2005

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The factors driving resistance to antiestrogens are unknown. Comparing the transcriptomes of antiestrogen responsive and resistant MCF-7 variants by serial analysis of gene expression, we have implicated several genes, including the human X-box binding protein-1 XBP-1. XBP-1 is a cAMP response element CRE binding protein associated with estrogen receptor ER expression in gene expression profiles of human breast cancers. We hypothesize that overexpression of XBP-1 andor activation of CRE contribute functionally to the ability of responsive cells to survive the metabolic stresses induced by exposure to antiestrogens. We also hypothesize that measuring expression of the XBP-1 protein will assist in better identifying antiestrogen resistant andor responsive tumors. Aim 1 We will further study the likely functional role of XBP-1CRE by overexpression through transfection into responsive cells, and inhibiting expression in resistant cells using novel CRE oligonucleotide decoys, antisense andor ribozymes. Effects of these molecular manipulations on responsiveness to antiestrogens will be studied in vitro and in vivo. Aim 2 We will explore the prognostic and predictive significance of XBP-1 expression in a unique series of human breast cancer biopsies. Thus, we will assess the extent to which XBP-1 is an independent prognostic factor, and whether it is associated with response to antiestrogens. Where possible, we will explore whether XBP-1 expression data allow us to build better predictiveprognostic models.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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