We have developed a unique transgenic mouse model system in which 100% of female mice carrying the C3(1)Tag transgene develop mammary cancer and male mice develop lesions in the prostate ranging from prostatic intraepithelial neoplasia to invasive carcinomas. This model offers the opportunity to study the multistep progression of tumorigenesis in these two important organ systems and determine molecular events which may be common or unique in mammary and prostate cancer development. We have identified several oncogenes and suppressor genes whose expression is altered during tumorigenesis. Comparative genomic hybridization has revealed specific chromosomal regions which are amplified during mammary cancer formation. The ras family of oncogenes may be particularly important in this process in both tumor types. Alterations in levels of apoptosis during mammary tumorigenesis have also been analyzed and have revealed that there is a dramatic increase in apoptosis during the transition from the normal to the hyperplastic stage. However, this critical protective response is lost as the cells progress from hyperplasia to invasive mammary carcinomas. The regulation of apoptosis in the prostate during tumorigenesis does not appear to follow a similar course as that in the mammary gland, but apoptosis levels continue to rise during prostate cancer development. We are currently seeking to understand what molecular alterations may contribute to the regulation of apoptosis in these tumors. Our work has also demonstrated that hormone manipulations affect the natural history of the disease processes in these transgenic mice which may, in part, result from alterations in the expression of various oncogenes and suppressor genes. We are also attempting to determine whether the in vivo immune response against mammary and prostate tumors can be augmented and used as a model of immunotherapy in these animals. Although various efforts have been unsuccessful in breaking immune tolerance in these mice, the combination of IL-2 and IL-12 has resulted in significant mammary tumor regression. This may, in part, be mediated by immune and non-immune mechanisms which we are attempting to elucidate.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005740-04
Application #
2463682
Study Section
Special Emphasis Panel (LMO)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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