Jeffrey E. Green, M.D.

Jeff Green received his M.D. from McGill University and residency training in pediatrics at the Children's Hospital of Philadelphia. He joined the NIH Clinical Center in 1984 as a clinical genetics fellow and subsequently became a Biotechnology post-doctoral fellow in the laboratory of the late George Khoury. Following an appointment as an Investigator in the Laboratory of Molecular Oncology at FCRDC, he joined the Laboratory of Cell Regulation and Carcinogenesis, NCI, in 1997 where he has served as the Head of the Transgenic Oncogenesis Group.

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 goal is to define what molecular events are involved in tumor progression and how this information may be used for targeting novel therapies to prevent cancer development or to inhibit tumor progression.

We have been pursuing a systems biology approach to characterize molecular changes that occur during breast and prostate cancer progression. Although cancer may be initiated by the dysregulation or mutation of certain genes, a better understanding of oncogenesis will emerge as clusters of genes that operate in a coordinated fashion are identified and their biologic functions are deciphered. Additionally, the gene networks that connect such clusters of genes need to be discovered, as they may be the critical targets to consider for therapeutic intervention. High throughput genomic approaches offer the potential to uncover this complexity.

In pursuit of these goals, our laboratory has emphasized gene expression profiling, comparative genomic hybridization, and more recently, proteomics, as a means of exploring the complexity of cancer and how the cancer genome evolves. Using animal models with well defined genetic lesions, we are identifying gene sets which tend to be dysregulated in common among many different mammary or prostate cancer models as well as gene clusters whose signatures help define tumors containing particular oncogenic lesions. These approaches have led us to identify sets of “cancer genes” for both mammary and prostate tumors as well as gene signatures specific to particular oncogenes (SV40 Tag, myc, ras, her2/neu, Polyoma middle T) and suppressor genes (p53, BRCA1, Rb).

Several microarray studies have been performed which define gene expression during normal mammary development as well as during progression of mammary cancer. A significant observation is that very few expression changes are identified between pre-invasive and invasive tumors and metastases. Genes responsive to estrogen, progesterone and prolactin have been identified in vivo. A signature which defines ER+ and ER- mammary tumors in both mouse and human has been identified. We have demonstrated that the addition of mouse array data to human data has significantly improved the class predictor for ER status in human tumors, a finding with important implication. Additionally, we have been able to classify tumors from mouse mammary cancer models in categories identified for human breast cancers, which is a major advance in understanding how these models relate to human disease. This will have high impact in determining how to use these models for pre-clinical testing. Similarly, androgen-responsive genes have been identified in two lobes of the prostate. These data are being analyzed in the context of functional changes that occur during the transition from hormone-dependent to hormone-independent tumors in both the mammary and prostate glands.

Additionally, we have determined what are the major molecular differences between chemically-induced or transgenically-driven prostate tumors using rat models. Understanding the molecular transition from hormone-dependent to hormone-independent tumor growth in both mammary and prostate cancers is also being pursued using gene expression profiling to define hormone-responsive genes and pathways.

We have also recently begun to analyze a set of over 200 human gastric cancer tumors including matched samples pre-and post-treatment with extensive follow-up. This will provide potentially valuable information for predicting tumor outcome based upon array signatures and response to therapy.

Since progression to metastasis is generally the critical step leading to patient mortality, we are also interested in using genomic tools to define what is necessary for metastasis to occur. Additionally, using in vitro and in vivo model systems, we are exploring how dormant metastatic cells are triggered to enter a proliferative phase and manifest clinically as metastases. Our lab is the first to develop an in vitro model for tumor cell dormancy and metastases which will have high impact in the field of metastases. We have identified the ECM as an important determining factor in the maintenance of dormancy as well as a specific integrin and signaling cascade as key to the escape from dormancy. These insights provide potentially important new targets for inhibiting mammary cancer progression which can be translated to the human disease.

Genetically-engineered animal models (GEM) offer an important and largely unexplored means for the pre-clinical testing of novel compounds and therapies. The C3(1)/Tag model of mammary and prostate cancer developed in our lab has been very useful for studying molecular oncogenesis as well as for certain preclinical therapeutic application, since tumor progression is extremely well defined in this model. Male C3(1)/Tag transgenic mice develop prostatic intraepithelial neoplasia (PIN) lesions very similar to those observed in humans, which often progress over several months to invasive adenocarcinomas. 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. A growing number of both chemopreventive compounds as well as anti-angiogenic agents have been tested in this model system and shown to have efficacy. We have continued to determine responses to preventive agents related to selenium, isothiocyanates, COX-2 inhibitors, and 2-methoxyestradiol for mammary cancer which all have potential translational potential to humans. New targets of COX-2 action (MAPK and ERK inhibition) have been identified in vivo. Of significance, we are the first to demonstrated that 2-methoxyestradiol leads to mammary gland differentiation, possibly in part, through downregulation of ID-1. Current studies are focused on combination therapies and using expression profiling to more clearly define molecular mechanisms which mediate these beneficial effects. The appropriate use of GEM models will inevitably lead to improved translational research and benefits to cancer patients. Our lab also emphasizes the development of new transgenic models for prostate and mammary cancer and the development of new targeting vectors and strategies to improve heterologous gene expression in vivo.

Currently, I serve as the Principal Investigator of the NCI Mouse Models of Mammary Cancer Collective, which is part of the national NCI Mouse Models of Human Cancer Consortium. The NCI Mouse Collective is composed of 25 NIH investigators who have assembled into a highly interactive community to advance the understanding of breast cancer through the use of animal models. With support from the Mouse Collective, my laboratory is expanding our research focused on using cDNA microarray technologies to define genetic pathways and identify new genes which are involved in mammary and prostate tumor development. We are comparing the expression profile signatures of tumors from several major transgenic mouse models of mammary cancer with that of human breast cancer as part of the validation process for mouse models of human disease. Additionally, I have chaired the NCI Microarray Steering Committee, which has guided the implementation of microarray technologies at the NCI.

In summary, our research aims to understand cancer from a systems biology perspective, identify genes that are involved in tumor progression and metastases that may serve as important targets for therapy, and advance the applications of animal models for pre-clinical testing. For additional information about the laboratory, as well as useful links, click here. 

Last modified on March 24, 2006.
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