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. We have developed a highly novel approach of integrating microarray data from human cancer with that of mouse cancer models, and have discovered 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 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 this network must be targeted to kill tumors with this signature. These findings provide new opportunities for devising targeted therapies and testing them in mouse models validated for this purpose.We have also focused efforts on cancer prevention and therapeutic intervention. My group has demonstrated 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. A patent is pending for this discovery and we have been approached by both American and European entities to initiate clinical trials. We are currently attempting to isolate the active compound(s) for further evaluation and development and are conducting in vivo tumor studies. We have also demonstrated that 2-methoxyestradiol has anti-breast tumor activites at late stages of cancer progression, but can lead to accelerated tumor growth if given at early stages. Interestingly, we have discovered that this compound has differentiating activities on the mammary gland.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. In summary, my research program is helping to achieve major objectives of the NCI through our work to understand cancer from a systems biology perspective, identifying genes that are involved in tumor progression and metastases that may serve as important targets for therapy, and applying this knowlege for testing novel chemoprevention and therapeutic stategies.
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