Validation of the Estrogen Related Receptor as a therapeutic target in cancer

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Several members of the nuclear receptor superfamily of transcription factors have been implicated in the biogenesis and/or regulation of mitochondrial function. More specifically, recent work from many laboratories, including our own, has indicated that the orphan nuclear receptor Estrogen Receptor- Related Receptor-a (ERRa) regulates the expression of most of the nuclear encoded genes involved in fatty acid (3-oxidation and oxidative phosphorylation. In addition, we now have compelling data that indicate that this receptor is involved in the positive regulation of the TCA cycle, steroidogenesis, bile acid metabolism, angiogenesis, the hexose mono-phosphate shunt, mitochondrial amino acid transport, and that it also negatively regulates the rate limiting steps in the glycolytic pathway. The linking of ERRa activity to mitochondrial function has reinvigorated interest in this receptor sub-family as therapeutic targets in cancer, metabolic diseases and mitochondrial dystrophies. Because of their structural similarity to the canonical estrogen receptors (ERa and ERp), it has long been considered that the ERRs function as regulators of estrogen responsiveness. It now appears, however, that activities unrelated to ER signaling are an equally important facet of ERR biology. In this study a series of new technologies, which have been developed in our laboratory, will be used (a) to define the specific role(s) of ERRa in liver biology and (b) to determine whether the formation of different receptor-cofactor complexes are associated with different biological outcomes. This work will provide an understanding of the physiological roles of this receptor subclass and will establish a scientific framework upon which to build discovery programs aimed at developing tissue/process-selective ERR modulators. These objectives will be realized upon completion of the following specific aims: Aim 1: Definition of the physiological role(s) of ERRa in liver using customized coactivators as protein ligands Aim 2: Identification of the molecular components of the ERRa signaling pathways in liver Aim 3: Evaluation of the impact of cofactors on ERRa transcriptional activity Aim 4: Examination of the biological consequence(s) of differential cof actor recruitment by ERRa: A test of the coactivator hypothesis