Abstract C127: Crystal structure of the SIX1/EYA transcriptional complex reveals ways to inhibit SIX1-mediated breast tumorigenesis/metastasis.

Abstract

Abstract The Six1 homeoprotein and members of the Eya family of co-activators are thought to form a bipartite transcription factor that is important in development and disease. Six1 and Eya are highly expressed during development, but their expression is lost in most adult tissues. Interestingly, Six1 and Eya are re-expressed in a variety of cancers, where they are known to promote both transformation and metastasis. However, a means to target the complex has remained elusive due to the recognized difficulties in targeting transcription factors. Thus, the molecular details of the protein-protein interface and an understanding of whether complex formation is necessary for tumorigenesis/metastasis are critical to the development of novel anti-cancer therapies targeting the Six1/Eya complex. Here we describe the 1.9 Å resolution crystal structure of the Six1/Eya complex revealing unexpected protein binding interfaces. The interaction resembles that of the p53/HDM2 complex, with a single helix of Six1 binding in a hydrophobic groove in Eya, both distant from sites originally thought to be involved in the Six1/Eya interaction. Remarkably, we show that a single amino acid substitution in Six1, involving a residue in the Eya binding interface, is sufficient to inhibit complex formation and to inhibit properties associated with Six1-induced tumorigenesis/metastasis. Since Six1 and Eya are regulators of embryonic development and are scarcely expressed in adult tissues, inhibition of the Six1/Eya pathway likely will lead to limited side effects in the adult. In addition, since 50–90% of breast cancer patients over-express Six1, therapies targeting the complex are likely to benefit a significant proportion of breast cancer patients, and an even greater proportion of patients with metastatic disease. Together, our findings suggest that inhibiting the Six1-Eya helical interface is a potential mechanism to develop novel, anti-breast cancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C127.