SUN-005 DAX-1 Inhibition of Estrogen Receptor and Metastasis Target Genes in Estrogen Receptor Positive Breast Cancer Cells

Abstract

The association of estrogens with breast cancer has led to the development of drugs that block the action of estrogens to treat and prevent estrogen receptor (ER) positive tumors. However, many tumors eventually become resistant to these drugs. Future drug discovery requires the identification of novel targets in the ER signaling pathway. The identification of proteins that directly bind to ER may offer new therapeutic targets for the treatment of breast cancer. The orphan receptor, DAX-1 (Dosage Sensitive Sex Reversal Adrenal Hypoplasia Congenita on the X Chromosome, gene 1) has been shown to act as a corepressor of ERα actions in MCF7 breast cancer cells. In this study we investigated the expression of DAX-1 during progressive stages of invasive ductal carcinoma with known ER status. To define the effect of DAX-1 expression in ER positive breast cancer cells, we performed gene expression analysis using PCR arrays that were specific for human breast cancer gene targets, human estrogen receptor signaling targets and tumor metastasis targets. We found that adenovirus-mediated expression of DAX-1 inhibits MCF7 cell proliferation and blocks estradiol activation of specific ER target genes, including cyclin D1. Repression of the cyclin D1 gene in MCF7 cells is associated with the recruitment of DAX-1 to the cyclin D1 promoter. Furthermore, introduction of DAX-1 into MCF7 cells leads to cell cycle arrest and an increase in apoptosis. These results demonstrate that DAX-1 functions as a corepressor of ER action in MCF7 breast cancer cells by preventing the activation of growth promoting genes and decreasing the stimulation of cell proliferation in response to estrogens. These finding could have significant implications for future drug development strategies specifically aimed at ER interacting proteins such as DAX-1.