Novel estrogen receptor ligands from plant genomics

DESCRIPTION (provided by applicant): Plants produce many types of molecules, such as chalcones flavones and flavonones, that interact with human estrogen receptors (ERs). Some of these may have therapeutic value in different types of hormone-sensitive cancer, but the full capacity of the plant genome to generate such ligands has not been explored. This project uses a functional genomics approach in which activation of the human ER is functionally linked to expression of a green fluorescent protein (GFP) reporter construct, in a transgenic plant line. When a population of these plants is subjected to random "gain of function" mutations, those individual mutants that overproduce ER agonists should be readily identifiable by their green fluorescence. This phase 1 STTR aims to transfer this "in situ screening" technology from the whole plant to the level of single plant cells with a consequent massive increase in screening throughput. In addition, small modifications to the technology should enable identification of ligands that are ER antagonists. The resulting screening strategy will then be applied to a large mutant population of N tabacum protoplasts, and "positive" subpopulations of microcultures isolated for further study in phase 2. The aim is to make the underlying biotechnology of greater value as a drug discovery platform, particularly when applied to nuclear receptor ligands of potential value in cancer pharmacotherapy. Project Narrative: New drugs are needed to treat cancers such as breast cancers. Plants produce molecules that could be used in cancer treatment if identified and properly developed. The project uses promising new biotechnology methods to find molecules in plants that work even better than existing drugs so that these molecules can be further studied and possibly developed into the next generation of anti-cancer drugs.