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Most recently, the laboratory discovered that subcellular partitioning of Eya protein between nucleus and cytoplasm iscritical for normal eye development and that phosphatase function is predominantly required in the cytosol. Cooperativeinteractions between Eya and the Abelson (Abl) tyrosine kinase were found to be critical for photoreceptor axon guidance inthe Drosophila visual system, and that mechanistically, Abl-mediated phosphorylation of Eya provides a critical cytoplasmicretention signal that presumably recruits Eya phosphatase activity to relevant signaling complexes. Abl is well-known as apotent oncogene, and its normal role in regulating actin cytoskeleton dynamics suggests that further investigation of Eya-Ablinteractions may provide new insight into the signaling networks regulating cell adhesion, motility, and invasiveness.Cell Signaling &Gene RegulationGeoffrey Greene, PhDProfessor of The Ben May Department for Cancer ResearchThe overall goal of research in Dr. Greene’s laboratory is to elucidate the molecular mechanisms by which female steroidhormones regulate development, differentiation, cellular proliferation and survival in hormone responsive tissues andcancers, especially breast cancer. Estrogens modulate the expression of diverse regulatory proteins and growth factors viaone or both of two estrogen receptor subtypes (ERα and ERβ). The Greene laboratory is actively studying multiple aspects ofER action, using a combination of in vitro, cell-based, and animal models.Current areas of focus include: 1) Defining the molecular/structural mechanisms by which selective estrogen receptormodulators (SERMs) elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novelER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) characterizinga mouse knock-in model in which a mutated ERα does not recognize endogenous estrogens, but will respond to exogenoussynthetic ligands; 4) identifying the relative contributions and mechanisms of transcriptional versus rapid, nongenomic ERαactions in estrogen target tissues; 5) developing targeted nanoparticles for imaging and therapeutic applications, especiallyin breast/prostate cancers; 6) genome-wide mapping and characterization of ERα/β target genes (ER transcriptome); and 7)identification and characterization of protein components of the ER interactome. All of these projects have direct relevanceand application to breast and uterine cancer genesis, progression, treatment and prevention, as well as to the development ofcompounds that can be used for hormone replacement therapy in postmenopausal women.The laboratory recently generated an estrogen non-responsive estrogen receptor knock-in (ENERKI) mouse model to studythe role of ERα during endocrine and neuroendocrine development and mammary tumor genesis. The mutant ERα (G525L)that was introduced by gene replacement into these mice does not recognize endogenous estrogen but does recognizeexogenous synthetic estrogen agonists and antagonists, such as diethylstilbestrol (DES), propyl pyrazole triol (PPT) and4-hydroxytamoxifen (OHT). Mutant ERα can be turned on or off simply by giving mice DES or PPT, both potent estrogens.ERα signaling pathways that do not require ligand remain intact, allowing them to study these pathways as well. FemaleENERKI mice had hypoplastic uterine tissues and rudimentary mammary gland ductal trees. Females were infertile due toanovulation, and their ovaries contained hemorrhagic cystic follicles because of chronically elevated levels of LH.The ENERKI phenotype confirmed that ligand-induced activation of ERα is crucial in the female reproductive tract andmammary gland development. Growth factor treatments induced uterine epithelial proliferation in ovariectomized ENERKIfemales, directly demonstrating that ERα ligand-independent pathways were active. PPT treatments initiated at pubertystimulated ENERKI uterine development, whereas neonatal treatments were needed to restore mammary gland ductalelongation, indicating that neonatal ligand-induced ERα activation may prime mammary ducts to become more responsive toestrogens in adult tissues. This mouse is a useful model for in vivo evaluation of ligand-induced ERα pathways and temporalpatterns of response. Interestingly, DES did not stimulate an ENERKI uterotrophic response, possibly due to the upregulationof ERβ in ENERKI mice, which is exerting an antiproliferative function in the uterus. It remains to be determinedif the mammary gland is similarly affected by DES treatment. ENERKI mice will be crossed with several mouse modelsthat develop spontaneous mammary tumors to better understand the role of endogenous estrogen and ERα in mammarycancer genesis and progression. This model should also prove useful for studying the estrogen-mediated development andhomoeostasis of the reproductive tract, bone, cardiovasculature and central nervous system.UCCRC SCIENTIFIC REPORT 200917