Abstract 2533: Regulation of proliferation and metastasis gene expression by DAX-1 (NR0B1) in human breast cancer cells

Abstract

Abstract The orphan nuclear receptor DAX-1 (Dosage Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, critical region on the X chromosome, gene 1) is known to serve an important role early on in mammalian sex determination as well as in the regulation of expression of steroid hormones. While it is unclear whether DAX-1 functions independently, DAX-1 has been demonstrated to act as a repressor of many nuclear hormone receptors, including ER, AR, PR, LRH-1 and SF-1. DAX-1 plays a role in select adult tissues, including gonadal tissue. However, it has also been shown to play a role in several types of cancer, though its specific function is not well understood. For example, in some types of cancer DAX-1 expression is upregulated, while in other cancers it is highly downregulated or completely absent. In an effort to better understand DAX-1 function both in normal and disease states, we examined the actions of DAX-1 in MCF7 breast cancer cells, which do not express the DAX-1 gene. We probed three different PCR arrays (breast cancer genes, proliferation genes and metastatic genes) to determine which genes were influenced by DAX-1 expression. With the introduction of DAX-1 in ERα positive breast cancer cells (MCF-7), we find that DAX-1 inhibits cell proliferation and blocks estradiol activation of key cell cycle regulatory genes, such as cyclin D1, as well as important metastatic genes. We show that DAX-1 binds directly to ERα and the ERα-DAX-1 complex binds to the cyclin D1 promoter. The outcome of DAX-1 expression in MCF7 cells is cell cycle arrest through the repression of key cell cycle regulatory genes. These results demonstrate that DAX-1 functions as a corepressor of ERα in MCF7 breast cancer cells by preventing the activation of growth-promoting genes and decreasing cell proliferation in response to estrogens. These findings could have significant implications for future drug development strategies specifically aimed at ER-interacting proteins such as DAX-1. Citation Format: Christina Tzagarakis-Foster. Regulation of proliferation and metastasis gene expression by DAX-1 (NR0B1) in human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2533.