Stanley Lipkowitz, M.D., Ph.D.
My laboratory has two main areas of interest. 1) We study Cbl proteins, a family of ubiquitin ligases that negatively regulate signaling by receptor tyrosine kinases. 2) We investigate induction of apoptosis in breast cancer cells by TRAIL receptor agonists. I am an attending physician in the Women’s Malignancies clinic at NCI and in the Breast Cancer clinic at Walter Reed National Military Medical Center.
As Chief, I oversee the laboratory and clinical research in the WMB. Our goal is to integrate laboratory and clinical research findings into mechanism-based, hypothesis-driven clinical trials on patients with breast and gynecological malignancies.
1) Cbl proteins, 2) ubiquitin ligases, 3) receptor tyrosine kinases, 4) TRAIL, 5) apoptosis,
6) breast cancer
Molecular Control of Growth, Differentiation, and Death in Epithelial Cancer Cells
My laboratory studies signal transduction pathways that regulate growth and programmed cell death in epithelial cancer cells, with a focus on breast and ovarian cancer. We have three projects:
In the first project we are studying the function of Cbl proteins. Human epithelial malignancies frequently display deregulated tyrosine kinase activity. Understanding the mechanisms that regulate signaling by these kinases should uncover new ways to inhibit cancer cell growth. We are investigating the function of Cbl proteins, a family of proteins that regulate tyrosine kinase activity. Cbl proteins belong to the RING finger class of ubiquitin protein ligases (E3s) and function as E3s for activated tyrosine kinases. My group cloned two of the three mammalian Cbl genes (Cbl-b and Cbl-c). We have shown that all mammalian Cbl proteins mediate ubiquitination and degradation of the activated EGFR as well as other components of the signaling complex. Ongoing work is focused on understanding the biochemical and physiologic functions of the three mammalian Cbl proteins in epithelial cells and elucidating the differences in their specificity and/or function.
Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. In a second project we are investigating the induction of apoptosis by activation of death receptors for the ligand TRAIL in breast and ovarian cancer cells. Our goal is to selectively trigger apoptosis in the cancer cells. We have shown that most breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-ErbB-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells.
Breast cancer tumors that do not express hormone receptors or have amplification of Her2/Neu (so called triple-negative tumors) have a poor prognosis and no validated molecular targets. In our third project we are using functional genomic approaches and tumor genetics to identify new therapeutic targets in triple-negative breast cancer cells.
Selected Key Publications
- Cancer Res. 59: 734-41, 1999. [ Journal Article ]
Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.Mol. Cell. 4: 1029-40, 1999. [ Journal Article ]
- Nature. 403: 211-6, 2000. [ Journal Article ]
- J Biol Chem. 276: 27677-84, 2001. [ Journal Article ]
- Breast Cancer Res. Treat. 113: 217-230, 2009. [ Journal Article ]
Stan Lipkowitz received an A.B. in 1977 and an M.D. and Ph.D. in 1984 from Cornell University. He trained in internal medicine at the New York Hospital and came to the NCI as a medical oncology fellow in 1987. After completing a fellowship, he established his own laboratory which studies the molecular and cell biology of epithelial cancer cells. Dr. Lipkowitz is also an adjunct Professor of Medicine and an adjunct faculty member of the Molecular and Cell Biology Graduate Program at the Uniformed Services University of the Health Sciences.
|Silvano Rakeem Daniels||Postbaccalaureate Fellow (CRTA)|
|Mireya Gomez||Patient Care Coordinator (Contr.)|
|Yoshimi Endo Greer, M.D., Ph.D.||Staff Scientist|
|Nicole D. Houston B.S.N., R.N., CCRP||Research Nurse|
|Fatou Hughes||Branch Secretary|
|Manjari Kundu Sil Ph.D.||Postdoctoral Fellow (Visiting)|
|Ann McCoy R.N.||Research Nurse|
|Erin Nichols R.N.||Research Nurse (Contr.)|
|Kathryn Trewhitt CRNP||Nurse Practitioner|
|Donna M. Voeller||Research Chemist|
|David Wisnewski Ph.D.||Postdoctoral Fellow (CRTA)|