Skin Diseases Research Center, Yale
The HER-2/Neu/ErbB-2 receptor tyrosine kinase is a major human oncogene and a validated therapeutic target in breast cancer. We are investigating the normal and carcinogenic functions of HER2 and other EGF receptor family kinases to understand how they cause cancers and how they can best be treated. We are also beginning to study the biology of other forms of breast cancer. This work includes use of cell biological, animal, and human models. Checkpoint controls are quality controls that supervise cell cycle progression and maintain genome stability. We are investigating signal transduction in yeast and human DNA checkpoint controls and the implications for cancer therapy. An important practical problem with new, targeted cancer therapies is linking patients to therapies that match the specific alterations in their cancers. We are pursuing high throughput genetic and proteomic approaches to this problem.
Extensive Research Description
1. 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/Trastuzumab and Tykerb/Lapatinib. 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).
2. 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.
3.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, lung cancer, pancreatic cancer, and melanoma.
- EGF Receptor activates MET through MAP kinases to enhance non-small cell lung carcinoma invasion and brain metastasis. Breindel JL, Haskins JW, Cowell EP, Zhao M, Nguyen DX, Stern DF. Cancer Res. 2013 Jun 21. [Epub ahead of print]
- MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF. Pigment Cell Melanoma Res. 2013 Jul;26(4):527-41. doi: 10.1111/pcmr.12
- Genotype-selective combination therapies for melanoma identified by high-throughput drug screening. Held MA, Langdon CG, Platt JT, Graham-Steed T, Liu Z, Chakraborty A, Bacchiocchi A, Koo A, Haskins JW, Bosenberg MW, Stern DF. Cancer Discov. 2013 Jan;3(1)
- Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Szno
- Wilson, K.A.*, Colavito*, S.A., Schulz, V., Wakefield T., Sessa W., Tuck, D. and D.F. Stern. 2011. NFBD1/MDC1 regulates Cav1 and Cav2 independently of DNA damage and p53. Mol Cancer Res 9:766-801. PMID: (21551225) *Authors contributed equally.
- Tworkoski, K., Singhal, G.*, Szpakowski*, S., Zito*, C.I., Bacchiocchi, A., Bosenberg, M, Krauthammer, M., Halaban, R., and D.F. Stern. 2011. Phospho-Proteomic Screen Identifies Potential Therapeutic Targets in Melanoma. Mol Cancer Res 9:801-12. PMID: (2
- Gilmore-Hebert, M., Ramabhadran, R, and DF. Stern. 2010. Interactions of ErbB4 and Kap1 connect growth factor and DNA damage response pathways. Mol Cancer Res 8:1388-98. PMID: (20858735)
- Agarwal,S, Zerillo,., Kolmakova, J., Christensen, JG, Harris, LN, Rimm, DL, DiGiovanna, MP, David F. Stern (2009) Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/HER2 inhibitor in non-small-ce
- David F. Stern 2009. BRCTing Up is Hard to Do, Molecular Cell, 33, 137-138.
- Stern DF. 2008. ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer. J Mammary Gland Biol Neoplasia. 13:215-23
- 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
- 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
- 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
- Wilson, KA, Stern, DF 2008. NFBD1/MDC1,53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway. Cell Cycle 7:3584-94
- Jackson-Fisher AF, Bellinger, G, Breindel, JL, Tavassoli FA, Boother CJ Duong, JK, Stern, DF 2008. ErbB3 is required for ductal morphogenesis in the mouse mammary Gland. Breast Cancer Res. 10:R96.