The focus of these studies is to determine molecular mechanisms involved in prostate and mammary tumorigenesis using transgenic mouse approaches, and to use these animal models as systems in which to test novel therapies. A primary objective of this work is understanding what molecular events are involved in tumor progression. To this end, we have concentrated our efforts on correlating the histogenesis of mammary and prostate lesions to molecular alterations that occur during the multistep process of carcinogenesis using several transgenic mouse models for these cancer including the C3(1)/Tag transgenic model developed in our lab. The transgenic models share important molecular and histopathologic similarities to those found in human breast and prostate cancer. We are interested in determining what genomic and genetic changes occur during mammary and prostate tumor progression in these models and relating these changes to those which occur in human cancers. Comparative genomic hybridization has demonstrated that mammary tumor progression is associated with an amplification on chromosome 6 resulting in the amplification and overexpression of the ki-ras oncogene associated with an elevation of MAP kinase activity and augmentation of tumor progression. Current efforts are focused on determining changes in gene expression profiles during tumor progression using cDNA microarray technologies. We have compared several models of mammary cancer in which tumors are initiated by different genetic events to identify oncogene-specific tumor signatures, identification of new genes involved in oncogenesis , and correlations to gene expression changes which occur in human breast and prostate cancer. This work provides important insights into mouse model validation for human cancers as well as identifying potential new targets for anti-cancer therapies. Important changes in the expression of genes that regulate the cell cycle have been identified, in particular, the loss of p21. Recent gene therapy approaches in our lab have demonstrated that the resotration of p21 function can significantly reduce mammary tumor progression using this transgenic mocdel. We have also demonstrated that (I)bax(/I) expression is critical to protective apoptosis primarily during preneoplasia. Double transgenic mice lacking bax have a significantly accelerated progression of mammary tumors. The role of sex hormones on both mammary and prostate tumor development are also being investigated. Hormone manipulations can lead to striking changes in the histopathologic phenotype of the mammary tumors. We have demonstrated that cancer progression in our transgenic model for mammary cancer is associated with loss of estrogen-receptor alpha expression as is the case in many human cancers. Understanding mechanisms of the down-regulation of ER expression is an additional focus of our work. We have also studying how pregnancy may alter the natural history of tumor progression in this model. Our lab is also using in vitro and in vivo systems to explore how androgen receptor may be invovled in prostate cancer progression. Our laboratory is using transgenic models for pre-clinical testing of chemopreventive and chemotherapuetic agents. We have demonstrated that several compounds are efficacious in inhibiting tumor progression as well as inhibiting angiogenesis. Current studies are exploring the molecular mechanisms of these effects using microarray approaches and advanced bioinformatics. In addition, we have developed new approaches and vectors using cre-lox technologies and inducible expression systems which will facilitate the generation of animal models with complex genetic alterations and improve gene expression delivery systems for gene therapy applications.
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