X-Box Binding Protein-1 in Breast Cancer

摘要

The factors driving resistance to antiestrogens are unknown. Comparing the transcriptomes of antiestrogen responsive and resistant MOF-7 variants by serial analysis of gene expression, we have implicated several genes, including the human X-box binding protein-I (XBP-I). XBP-I is a cAMP response element (ORE) binding protein associated with estrogen receptor (ER) expression in gene expression profiles of human breast cancers. We hypothesize that overexpression of XBP-I andlor activation of ORE 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-I protein will assist in better identifying antiestrogen resistant andlor responsive tumors. Aim I :We will further study the likely functional role of XBP- IlORE by overexpression through transfection into responsive cells, and inhibiting expression in resistant cells. Effects of these molecular manipulations on responsiveness to antiestrogens will be studied. We will; also identify signaling downstream of XBPI that may explain how XBPI modifies responsiveness to endocrine treatments in breast cancer cells. Aim 2: We will explore the prognostic and predictive significance of XBP-I expression in a unique series of human breast cancer biopsies. Thus, we will begin to assess the extent to which XBP-I is a candidate prognostic factor.