Our primary focus 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 question 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 the C3(1)/Tag transgenic model developed in our lab. Male C3(1)/Tag transgenic mice develop prostatic intraepithelial neoplasia (PIN) lesions very similar to those observed in humans, which often progress to invasive adenocarcinomas over several months. 100% of female mice carrying the C3(1)/Tag transgene develop mammary adenocarcinomas over several months in a very predictable manner demonstrating transition lesions similar to DCIS found during human breast cancer development. We are using this to compare mechanisms of tumorigenesis in two different hormone-dependent tissues within the same genetic background. One focus of our work has been to determine what genetic changes in addition to the expression of SV40-T-Ag occur during mammary and prostate tumor progression in this model. Using comparative genomic hybridization, we have 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. Double transgenic mice lacking ki-ras have a delayed onset of mammary tumor formation, demonstrating the importance of ki-ras in tumor progression. Preliminary CGH analyses of prostate cancer indicates that other regions of amplification and deletions may be involved. We have demonstrated that Ha-ras mutations are rare in our transgenic mammary tumors but frequent in tumors of the prostate. Further genetic alterations are being identified by LOH at particular stages of tumor progression. 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 also studying how pregnancy may alter the natural history of tumor progression in this model. Our lab is also using (I) in vitro (/I) and (I) in vivo (/I) systems to explore how androgen receptor may be invovled in prostate cancer progression. The laboratory is in the process of developing and evaluating several new prostate-specific promoters that may be useful for targeting expression to the prostate in transgenic mice, as well as for gene therapy. In addition, microarray technolgies are being employed for gene discovery as well as to study how gene expression profiles change during both mammary and prostate tumor progression.
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