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Abstract
Grant Number: 5R01CA089041-08 Project Title: Mechanisms Regulating Reversal of Malignancy
PI Information: Name Title FURTH, PRISCILLA A. paf3@georgetown.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Our long-range goal is to establish the mechanisms underlying successful therapeutic approaches to reverse preneoplasia, identify genetic and molecular events that impair reversal, identify predictive biomarkers and translate results to people. This Project will exploit unique conditional mouse models of breast and salivary gland cancer to define the role of p53 in pharmacological differentiation therapies that target nuclear receptors Retinoid X Receptor alpha (RXRalpha) and Peroxisome proliferator-activated receptor gamma (PPARgamma). Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed and perhaps metastatic cancer. The central hypothesis of this proposal is that ligand induced activation of RXRalpha and PPARgamma in epithelial cells can impel resolution of refractory dysplasia through a re-differentiation process that involves down-regulation of Protein Phosphatase 2A (PP2A) activity. A secondary hypothesis is that normal p53 function contributes to the re-differentiation process initiated by RXRalpha and/or PPARgamma agonists. Hypothesis: The mechanism by which pharmacological activation of RXRalpha and/or PPARgamma in epithelial cell preneoplasia in vivo leads to successful disease reversal is through cell cycle arrest and differentiation mediated by down- regulation of PP2Ac, DP-1 phosphorylation, decreased CDK-2, increased p27, increased p53 activity, and decreased collagen production with changes in the extracelllalr matrix. Additional mechanisms that will be activated in ERalpha positive mammary preneoplasia include down-regulation of ERalpha and cyclin D1, up- regulation of Brca1 and decreased collagen production with changes in the extracellular matrix. Specific Aims: 1. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination are able to redifferentiate refractory dysplastic salivary tissue in GRIDS mice through down-regulation of PP2Ac expression with secondary gain of DP-1 phosphorylation, loss of CDK-2, and increased p27 expression. 1. b. Test if normal p53 expression levels contribute to successful reversal by these pharmacological agents. 2. a. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination redifferentiate ERalpha-expressing ductal hyperplasia and DCIS in CERM mice through down-regulation of PP2Ac, gain of DP-1 phosphorylation, increased p27 and loss of CDK-2 and/or through loss of ERalpha, cyclin D1 and increased Brca1. Compare histological and molecular responses to the RXRalpha and/or PPARgamma agonists with the ERalpha antagonist tamoxifen and conditional down-regulation of the ERalpha transgene. 2. b. Test if normal p53 expression contributes to successful reversal by pharmacological RXR and/or PPARgamma agonists, the ERalpha antagonist tamoxifen and/or conditional down-regulation of the ERalpha transgene. 2. c. Test if pharmacological RXRalpha and/or PPARgamma agonists alone or in combination prevent development of ERalpha ductal hyperplasia and DCIS.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
adenocarcinoma, neoplastic process, oncoprotein, preneoplastic state, viral carcinogenesis
Bax gene /protein, gene induction /repression, mouse mammary tumor virus, neoplasm /cancer genetics, nucleic acid repetitive sequence, p53 gene /protein, simian virus 40, tumor antigen, virus genetics, virus protein
genetically modified animal, laboratory mouse
Institution: GEORGETOWN UNIVERSITY 37TH AND O STS NW WASHINGTON, DC 20057 Fiscal Year: 2007 Department: ONCOLOGY Project Start: 30-AUG-2006 Project End: 31-MAY-2010 ICD: NATIONAL CANCER INSTITUTE IRG: CDP