Jeffrey E. Green, M.D.
Jeffrey E. Green, M.D.
Senior Investigator
Head, Transgenic Oncogenesis and Genomics Section

Center for Cancer Research
National Cancer Institute

Building 37, Room 4054C
Bethesda, MD 20892
301-435-5193

Our primary focus is to determine molecular mechanisms involved in mammary tumorigenesis using transgenic mouse approaches, and to use these animal models as systems in which to test novel therapies. A major goal is to further identify molecular events that 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 high throughput genomic approaches to characterize molecular changes that occur during breast and prostate cancer progression.

Areas of Expertise
transgenic mice, tumor progression

Transgenic Models for Prostate and Mammary Carcinogenesis

Our primary focus is to determine molecular mechanisms involved in mammary tumorigenesis using transgenic mouse approaches, and to use these animal models as systems in which to test novel therapies. A major goal is to further identify molecular events that 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 high throughput genomic approaches 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 networks of genes are identified that operate in an integrated fashion and their biologic functions are deciphered. Additionally, the genetic nodes that connect such networks are of particular interest since they may be critical targets for therapeutic intervention. High throughput genomic approaches offer the potential to begin to unravel this complexity.

In pursuit of these goals, our laboratory has utilized mRNA and miRNA expression profiling and comparative genomic hybridization to obtain a more global genomic picture of cancer evolution. 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 gene signatures for several genetically-engineered animal models carrying genetic aberations that are relevant to human cancer, including models generated through the overexpression of myc, ras, her2/neu or Polyoma middle T and other models where suppressor gene function has been impaired for p53, Rb, and BRCA1.

Several microarray studies have been performed which define gene expression during normal mammary development as well as during progression of mammary cancer. We have observed that very few expression changes are identified between pre-invasive and invasive tumors and metastases. Using a cross-species analysis approach, we have identified a signature that defines ER+ and ER- mammary tumors in both the mouse and human and have demonstrated that the addition of mouse array data to human data significantly improved the class predictor for ER status in human tumors. Through cross-speicies comparisons, we have been able to identify specific molecular similarities between several mouse mammary cancer models and sub-types of human breast cancers. This provides an important means of credentialling some models for pre-clinical testing with relevance to sub-types of human breast cancer.

We are now using this information to identify novel targets in triple-negative (TN) basal-type breast cancer and test their therapeutic efficacy in the C3(1)/Tag transgenic model that was previously developed in our lab. The C3(1)/Tag model of mammary and prostate cancer has been very useful for studying molecular changes involved in basal TN breast cancer as well as for certain preclinical therapeutic applications, 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 have demonstrated efficacy. This model is also being used to identify chemoresistance signatures that may develop in response to drugs used to treat TN basal breast cancer. We have recently completed genomic analyses using gene expression profiling and array CGH of human gastric cancer tumors that has allowed us to identify both primary and acquired gene predictors of therapeutic response to cisplatin/5-FU therapy. This will provide potentially valuable information for predicting tumor outcome based upon array signatures and response to therapy.

Since progression to metastasis and tumor recurrence are critical steps leading to patient mortality, we are exploring how dormant metastatic cells are triggered to enter a proliferative phase and manifest clinically as metastases. Our lab recently reported the development of an in vitro model predictive for in vivo tumor cell dormancy or proliferation which is being used to further define mechanisms that regulate the dormant-to-proliferative switch. We have demonstrated that the ECM is an important determining factor in the maintenance of dormancy or switch to proliferation and that the integrin signaling cascade plays a key role in regulating this process. We continue to explore how the microenvironment influences the maintenance of tumor cell dormancy or proliferative outbreak.

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.

Scientific Focus Areas:
Cancer Biology, Cell Biology, Genetics and Genomics, Molecular Biology and Biochemistry, Systems Biology
Selected Recent Publications
  1. El Touny LH, Vieira A, Mendoza A, Khanna C, Hoenerhoff MJ, Green JE.
    J Clin Invest. 124: 156-68, 2014. [ Journal Article ]
  2. Kim HK, Green JE.
    Pharmacogenomics. 15: 375-84, 2014. [ Journal Article ]
  3. Chu IM, Lai WC, Aprelikova O, El Touny LH, Kouros-Mehr H, Green JE.
    PLoS ONE. 8: e61125, 2013. [ Journal Article ]
  4. Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW.
    PLoS ONE. 8: e72287, 2013. [ Journal Article ]
  5. Ahn SG, Dong SM, Oshima A, Kim WH, Lee HM, Lee SA, Kwon SH, Lee JH, Lee JM, Jeong J, Lee HD, Green JE.
    Breast Cancer Res Treat. 141: 89-99, 2013. [ Journal Article ]

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 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 Biology and Genetics (formerly Laboratory of Cell Regulation and Carcinogenesis) where he serves as the Chief of the Transgenic Oncogenesis and Genomics Section.

Name Position
Olga Aprelikova, Ph.D. Staff Scientist
Michelle Bradley Summer Student
Constance Brignatz-Guittard Postdoctoral Fellow (Visiting)
Kenny Chen Student Intern
Lara El Touny Research Fellow
Dong Min Ph.D. Special Volunteer
Ryan Nini Postbaccalaureate Fellow
Ting-Hu Qiu Ph.D. Research Biologist
Laura Vera Ramirez Ph.D. Postdoctoral Fellow (Visiting)

Summary

Our primary focus is to determine molecular mechanisms involved in mammary tumorigenesis using transgenic mouse approaches, and to use these animal models as systems in which to test novel therapies. A major goal is to further identify molecular events that 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 high throughput genomic approaches to characterize molecular changes that occur during breast and prostate cancer progression.

Areas of Expertise
transgenic mice, tumor progression

Research

Transgenic Models for Prostate and Mammary Carcinogenesis

Our primary focus is to determine molecular mechanisms involved in mammary tumorigenesis using transgenic mouse approaches, and to use these animal models as systems in which to test novel therapies. A major goal is to further identify molecular events that 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 high throughput genomic approaches 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 networks of genes are identified that operate in an integrated fashion and their biologic functions are deciphered. Additionally, the genetic nodes that connect such networks are of particular interest since they may be critical targets for therapeutic intervention. High throughput genomic approaches offer the potential to begin to unravel this complexity.

In pursuit of these goals, our laboratory has utilized mRNA and miRNA expression profiling and comparative genomic hybridization to obtain a more global genomic picture of cancer evolution. 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 gene signatures for several genetically-engineered animal models carrying genetic aberations that are relevant to human cancer, including models generated through the overexpression of myc, ras, her2/neu or Polyoma middle T and other models where suppressor gene function has been impaired for p53, Rb, and BRCA1.

Several microarray studies have been performed which define gene expression during normal mammary development as well as during progression of mammary cancer. We have observed that very few expression changes are identified between pre-invasive and invasive tumors and metastases. Using a cross-species analysis approach, we have identified a signature that defines ER+ and ER- mammary tumors in both the mouse and human and have demonstrated that the addition of mouse array data to human data significantly improved the class predictor for ER status in human tumors. Through cross-speicies comparisons, we have been able to identify specific molecular similarities between several mouse mammary cancer models and sub-types of human breast cancers. This provides an important means of credentialling some models for pre-clinical testing with relevance to sub-types of human breast cancer.

We are now using this information to identify novel targets in triple-negative (TN) basal-type breast cancer and test their therapeutic efficacy in the C3(1)/Tag transgenic model that was previously developed in our lab. The C3(1)/Tag model of mammary and prostate cancer has been very useful for studying molecular changes involved in basal TN breast cancer as well as for certain preclinical therapeutic applications, 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 have demonstrated efficacy. This model is also being used to identify chemoresistance signatures that may develop in response to drugs used to treat TN basal breast cancer. We have recently completed genomic analyses using gene expression profiling and array CGH of human gastric cancer tumors that has allowed us to identify both primary and acquired gene predictors of therapeutic response to cisplatin/5-FU therapy. This will provide potentially valuable information for predicting tumor outcome based upon array signatures and response to therapy.

Since progression to metastasis and tumor recurrence are critical steps leading to patient mortality, we are exploring how dormant metastatic cells are triggered to enter a proliferative phase and manifest clinically as metastases. Our lab recently reported the development of an in vitro model predictive for in vivo tumor cell dormancy or proliferation which is being used to further define mechanisms that regulate the dormant-to-proliferative switch. We have demonstrated that the ECM is an important determining factor in the maintenance of dormancy or switch to proliferation and that the integrin signaling cascade plays a key role in regulating this process. We continue to explore how the microenvironment influences the maintenance of tumor cell dormancy or proliferative outbreak.

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.

Scientific Focus Areas:
Cancer Biology, Cell Biology, Genetics and Genomics, Molecular Biology and Biochemistry, Systems Biology

Publications

Selected Recent Publications
  1. El Touny LH, Vieira A, Mendoza A, Khanna C, Hoenerhoff MJ, Green JE.
    J Clin Invest. 124: 156-68, 2014. [ Journal Article ]
  2. Kim HK, Green JE.
    Pharmacogenomics. 15: 375-84, 2014. [ Journal Article ]
  3. Chu IM, Lai WC, Aprelikova O, El Touny LH, Kouros-Mehr H, Green JE.
    PLoS ONE. 8: e61125, 2013. [ Journal Article ]
  4. Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW.
    PLoS ONE. 8: e72287, 2013. [ Journal Article ]
  5. Ahn SG, Dong SM, Oshima A, Kim WH, Lee HM, Lee SA, Kwon SH, Lee JH, Lee JM, Jeong J, Lee HD, Green JE.
    Breast Cancer Res Treat. 141: 89-99, 2013. [ Journal Article ]

Biography

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 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 Biology and Genetics (formerly Laboratory of Cell Regulation and Carcinogenesis) where he serves as the Chief of the Transgenic Oncogenesis and Genomics Section.

Team

Name Position
Olga Aprelikova, Ph.D. Staff Scientist
Michelle Bradley Summer Student
Constance Brignatz-Guittard Postdoctoral Fellow (Visiting)
Kenny Chen Student Intern
Lara El Touny Research Fellow
Dong Min Ph.D. Special Volunteer
Ryan Nini Postbaccalaureate Fellow
Ting-Hu Qiu Ph.D. Research Biologist
Laura Vera Ramirez Ph.D. Postdoctoral Fellow (Visiting)