Understanding how particular oncogenic events may specify the development of particular sub-types of breast and prostate cancer has been a focus of our work. Mouse models of human cancers offer particular advantages in uncovering such relationships since specific genetic alterations can be utilized to induce tumorigenesis and variability in genomic changes can be minimized using mice with well-defined genetic backgrounds. Our progress includes: 1) development and utilization of novel approaches to integrate microarray data from both human cancer and corresponding mouse cancer models. These studies have demonstrated that specific mouse models of mammary cancer can be classified with human basal or luminal tumors according to the initiating oncogenic event. By performing the first supervised analysis comparing mouse and human breast cancers according their estrogen-receptor status, we have identified a robust and highly gene network related to breast cancer tumor lineage and estrogen receptor function that could not be uncovered using only human array data. Interestingly, this ER network is operative during normal mammary development, thus indicating that ER+ positive tumors utilize an existing signaling system found in normal mammary epithelium. We have also discovered an intrinsic oncogene signature for SV40 T/t-antigens in multiple epithelial transgenic tumors. This unique signature defines a highly integrated network related to DNA damage and repair, cell cycle regulation, proliferation and apoptosis. Importantly, this signature predicts poor prognosis and metastases in human breast, prostate and lung cancers, suggesting that targets identified by this network may be vital for tumor maintenance. These findings provide new opportunities for devising targeted therapies and testing them in mouse models validated for this purpose. We have made important observations related to cancer prevention and therapeutic intervention. Our group is the first to demonstrate that muscadine grape skin extract contains unique compounds that inhibit growth of transformed prostate cancer cells at least in part through inhibition of the Akt survival pathway. We are currently attempting to isolate the active compound(s) for further evaluation and development, and are conducting in vivo tumor studies. In order to understand how tumor cells switch from a dormant state to a proliferative metastatic state, we have developed that first in vitro predictive model system to study this phenomenon. We have discovered that the dormant state can be dependent upon the extracellular environment and that proteins determining the intracellular architecture of the cell are critical in regulating the switch from dormancy to proliferative metastatic growth. This system is being exploited to further understand mechanisms of dormancy and proliferative outbreak from dormancy. New insights from these studies may be extremely valuable in devising new strategies to kill dormant tumor cells or maintain their dormant phenotype, thus preventing metastatic recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005740-15
Application #
7592551
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2007
Total Cost
$2,222,881
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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