The broad objective of this project is to gain further understanding regarding the endocrinology of hormonal responses in women in order to provide rational design of therapies directed toward the clinical problems of endometriosis, pregnancy loss, fertility, and estrogen- dependent reproductive neoplasms. Advances during the current period include: 1) isolation of a novel RXR-binding protein from a breast cancer cDNA expression library; 2) demonstration that the novel RXR binding protein is present in breast cancer tissues and binds to the retinoid X receptor; 3) determination that mRNA for the novel protein is expressed in breast cancer cells in addition to other reproductive tissues; 4) demonstration that the novel protein and RXR interact in vivo using the dual hybrid yeast system; 5) demonstration that the retinoid X receptor interacts with the general transcription factor TFIIB in a yeast system; 6) determination of the regions required for RXR binding to TFIIB using GST binding assays and co-immunoprecipitation studies; 7) a demonstration that the interaction between RXR and the general transcription factor IIB requires ligand, and 8) demonstration of RXR activation of estrogen responsive genes in the presence of the perxisome proliferator-activated receptor (PPAR). We plan to further characterize the novel RXR-binding protein and study additional proteins that may contribute to modulation of estrogen responsive genes.
