Research
Human cancer is caused by genetic and epigenetic changes that alter hormone-regulated signal transduction pathways, leading to growth dysregulation, and that alter protective responses to DNA damage, leading to genomic instability. The Stern laboratory investigates processes that represent each of these major categories. The goals of this work are better understanding of the underlying causes of human cancer and linkage of this understanding to therapeutic applications.
A.EGF family receptor tyrosine kinases in cancer. Mutations
in these receptor genes cause subsets of breast cancer, lung cancer, glioma,
head and neck cancer, colorectal carcinoma, and other solid tumors. For
this reason, drugs targeting these receptors are among the most important
new cancer therapeutics. These drugs include Tarceva/Erlotinib, Tykerb/Lapatinib,
Erbitux/Cetuximab, and Herceptin/Trastuzumab. For example, the receptor
tyrosine kinase ErbB2/HER2 drives 25% of breast cancers. This receptor
is the target for two drugs in use for breast cancer treatment, Herceptin
and Tykerb. In order to understand why this receptor is so important in
human cancer, and to improve therapeutic targeting of ErbB2/HER2, we investigate
normal and pathological functions of this receptor in mammary tissue.
Our work spans from fundamental studies on signal transduction to analysis
of ErbB2 in human cancer. ErbB2 works in close partnership with other
members of the EGF receptor (ErbB family) of tyrosine kinases, so we also
study differential signaling by the three related receptors (EGF receptor
[HER]), ErbB3 [Her-3], ErbB4[Her4).
B.Checkpoint controls function as quality controls that supervise
cell cycle progression. Such controls are of great interest because of their
role in cell cycle regulation, and because they are commonly altered in human
cancer. We are investigating signal transduction in DNA checkpoint control
pathways. This involves analysis of checkpoint signaling in both budding yeast
and humans, with the focus on the double-strand DNA break response pathway
encompassing tumor suppressor gene Atm and Chk2/Rad53, and mediator proteins
NFBD1/MDC1, 53B1, BRCA1, and MCPH1.
C.Predicting sensitivity to molecularly targeted drugs. The growing availability of cancer drugs that target receptors and other signaling proteins has created a need to develop integrated methods for best matching of patients to the appropriate target drugs. We are investigating use of DNA-based and functional approaches for predicting response to targeted therapies, in breast cancer and melanoma.
Current projects.
1.ErbB4
is unique among receptor kinases in undergoing regulated cleavage to release
an active intracellular domain. We are studying the nature of nuclear processes
regulated by ErbB4, and the role of alternative splicing in generating functionally
diverse forms of the receptor.
2.Excessive
activity of growth factor receptors can lead to checkpoint arrest, selection
for checkpoint bypass, and genomic instability. We are investigating the hypothesis
that high-level signaling by ErbB2/HER2 promotes genomic instability, a hallmark
of breast cancer and other solid tumors.
3.Our laboratory
originally identified the importance of “mediator proteins” in transmission
of checkpoint responses from sensor phosphatidyl inositol kinase-like kinases
to effector checkpoint kinases through recognition of phospho-peptides. Ongoing
work includes understanding differential activities of mammalian mediators
(BRCA1, 53BP1, MDC1/NFBD1) in DNA damage responses, and reconstruction of
checkpoint signaling cascades using purified yeast checkpoint proteins.
4.In collaboration
with several other breast cancer researchers, we are analyzing molecular differences
of ductal carcinoma in situ that are associated with aggressive biological
properties leading to invasion or eventual relapse.
5.In collaboration
with Ruth Halaban, Mario Sznol, and other members of the Yale Skin SPORE,
we are evaluating the potential to predict melanoma treatment responses through
deep analysis of signal transduction processes and genetic changes.
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People
Current members of the Stern laboratory:
- Maureen Gilmore-Hebert, PhD, Associate Research Scientist
Nuclear functions of ErbB4 - Christina Zito, PhD, Postdoctoral Fellow
Signal transduction and cancer gene reseqencing analysis of melanoma and breast cancer - Kathleen Wilson, Graduate Student, USAMRMC Breast Cancer Research
Fellow
Differential activity of mammalian checkpoint mediator proteins - Jerrica Breindel, Graduate Student, USAMRMC Breast Cancer Research
Fellow
ErbB2/HER2 in checkpoint signaling and genomic instability - Kathryn Tworkoski, Graduate Student, National Science Foundation
Fellow
Signal transduction and knockdown analysis of melanoma - Neil Desai, Yale Medical and Howard Hughes Medical Institute
Fellow
Exon capture for cancer genome sequencing; biology of in situ carcinoma - Rahul Dalul, Undergraduate
- Garima Singhal, Visiting Graduate Student
- Patricia Wakefield, Visiting
Transcriptional analysis of mediator-dependent DNA damage responses. - Andrew Laudano, PhD, Visiting
faculty, from University of New Hampshire
Interaction of estrogen receptors with ErbB signaling in breast cancer
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Publications
Selected Recent Publications:
Stern DF. 2008. ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer. J Mammary Gland Biol Neoplasia. 13:215-23.
DiGiovanna MP, Stern DF, Edgerton S, Broadwater G, Dressler LG, Budman DR, Henderson IC, Norton L, Liu ET, Muss HB, Berry DA, Hayes DF, Thor AD. 2008. Influence of activation state of ErbB-2 (HER-2) on response to adjuvant cyclophosphamide, doxorubicin, and fluorouracil for stage II, node-positive breast cancer: study 8541 from the Cancer and Leukemia Group B. J. Clin Oncol 26:2364-72
Zito CI, Riches D, Kolmakova J, Simons J, Egholm M, Stern DF. 2008. Direct resequencing of the complete ERBB2 coding sequence reveals an absence of activating mutations in ERBB2 amplified breast cancer. Genes chromosomes Cancer 47:633-8
Jia-Lin Ma N, Stern DF. 2008. Regulation of the Rad53 protein kinase in signal amplification by oligomer assembly and disassembly. Cell Cycle 7: 808-17
Ma, J.L., Lee, S.J.,Duong, J.K., Stern, D.F. 2006 Activation of the Checkpoint Kinase Rad53 by the Phosphatidyl Inositol Kinase-like Kinase Mec1.J Biol Chem. 281(7):3954-63.
A.J. Jackson-Fisher, G. Bellinger, E. Shum, J.K. Duong, A.S. Perkins, M. Gassmann, W. Muller, K. Lloyd, and D.F. Stern. 2006. Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4. Oncogene 5:5664-72
*DiGiovanna, M.P. * Stern, D.F., Edgerton, S.,
Whalen, S.G., Moore II, D., and A.D. Thor. 2005. Relationship
of epidermal growth factor receptor expression to ErbB-2 signaling activity
and prognosis in breast cancer patients.
Journal of Clinical Oncology23:1152-60. *authors contributed equally to
this work
Tsvetkov, L., and D.F. Stern. 2005. Phosphorylation of Plk1 at S137 and T210 is inhibited in response to DNA damage. Cell Cycle 4:166-171.
Li, Jia., and D.F. Stern. 2005. Regulation of Chk2 by DNA-dependent protein kinase. J. Biol. Chem. 280:12041-50.
Tsvetkov, L., and D.F. Stern. 2005. Interaction of Chromatin-Associated Plk 1 and Mcm7. J. Biol. Chem. 280:11943-7.
Tsvetkov, L., Tsekova, R., Xu., X., and D.F. Stern. 2005. The Plk1 Polo Box domain mediates a cell cycle- and DNA damage-regulated interaction with Chk2. Cell Cycle. 4:609-617.
Amin, D., Tuck, D., and D.F. Stern. 2005. Neuregulin-regulated gene expression in mammary carcinoma cells. Experimental Cell Research 309:12-23.
D.F. Stern. Phosphoproteomics for Oncology Discovery and Treatment. 2005. Expert Opin Ther Targets. 9:851-60.
Li, Jia., and D.F. Stern. 2005. DNA Damage Regulates Chk2 Association with Chromatin. J.Biol.Chem.280:3748-56
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