acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

Both estrogen (E2), acting through the estrogen receptor (ER), and insulin-like growth factor 1 (IGF-1), through activation of the phosphatidylinositol-3-kinase (P13K)AKT pathway, have been shown to promote breast cancer through their abilities to enhance cancer cell survival. In this project, a crosstalk between the E2-ER and IGF1-PI3K-AKT pathways was investigated, and the impact of this crosstalk on breast cancer cell survival was assessed. These studies reveal that a survival crosstalk exists between these two pathways in the ability of AKT to regulate ER transcriptional activity. Furthermore, AKT, through its potentiation of ER activity, enhanced breast cancer cell survival in the presence of tumor necrosis factor alpha (TNF-alpha), a physiological inducer of apoptosis Since Bcl-2 is a pro-survival factor, the ability of the E2-ER/PI3K-AKT survival crosstalk to regulate Bcl-2 expression was investigated. These studies indicate that AKT potentiated Bcl-2 expression through the ERalpha, but not the ERbeta. More detailed studies reveal that AKT potentiated both activation function (AF) domains of ERalpha but only the AF-2 of ERbeta, indicating that differential regulation of ERalpha and ERbeta by AK T may influence the activity of each receptor isoform at the Bcl-2 promoter. Finally, addition of the coactivator glucocorticoid receptor-interacting protein 1 (GRIP-1) further enhanced Bcl-2 expression, indicating that coactivators may be involved in this E2-ER/PI3K-AKT survival crosstalk. Hence, AKT, through its potentiation of ERalpha, may enhance Bcl-2 expression, which may enhance cancer cell survival Given the importance of coactivators to ER activity, the ability of AKT to regulate coactivators was investigated. These results indicate that AKT enhanced steroid receptor coactivator 1 (SRC-1) and GRIP-1 binding to both the ERalpha and ERbeta, although the binding was more robust with ERalpha. AKT was also able to phosphorylate GRIP-1, possibly at the nuclear receptor binding domain (NRID) used for binding to the ER. Additionally, these studies reveal that AKT was able to potentiate the inherent activity of GRIP-1 through targeting the activation domain (AD) of the coactivator. Finally, these activation domains were shown to be required for AKT potentiation of the transcriptional activity of the ERalpha, although not of the ERbeta Collectively, these studies indicate that AKT potentiation of ER transcriptional activity is the result of multiple levels of regulation, since AKT targets not only the ER, but also the coactivators that interact with the ER. Hence, the ability of AKT to potentiate ER activity at the Bcl-2 promoter may contribute to breast cancer cell survival. In this E2-ER/PI3K-AKT survival crosstalk, the ER serves as a conduit through which both the E2 and IGF-1 signaling pathways converge. These results may provide clues into breast cancer etiology / acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

acase@tulane.edu

The Rational Expectations Hypothesis (REH) restricts short- and long-horizon forecasts to be consistent with one another. Cross-variable consistency, also imposed by the REH, is the requirement that contemporaneously formed expectations of different variables be consistent with one another, as well as with the 'true model' jointly determining the realizations of those variables. After reviewing the literature on direct tests of the REH employing survey data as proxies for unobservable expectations, this dissertation (1) defines cross-variable consistency, (2) derives a Fisher-equation model of the nominal interest rate and (3) conducts cross-variable consistency tests for rationality of the ASA/NBER-SPF survey forecasts of macroeconomic variables using the derived model. Results strongly confirm the rationality of the median predictions and generally support the conclusion that individual forecasters form expectations in a manner consistent with the REH / acase@tulane.edu

acase@tulane.edu

acase@tulane.edu