WASHINGTON UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICINE

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Alterations and constitutive activation of signal transduction pathways play a significant role in the growth and metastasis of human cancers. Proteomics is the large-scale identification and characterization of proteins and it can be used to provide deeper insights into these pathways by identifying novel proteins and sites of post-translational modifications. We focus on the Her2/neu receptor tyrosine kinase, a member of the EGFR growth factor receptor family, which is constitutively activated in 20-30% of human breast cancer cases. We have conducted a proteomic study of Her2/neu signaling and quantitatively measured the phosphorylation status of 462 proteins. The phosphorylation measurements were made using mass spectrometry and a labeling technique called SILAC (Stable Isotope Labeling using Amino Acids in Cell Culture). In this study, we identified many novel signaling proteins that may affect receptor endocytosis, receptor cross-talk, and downstream signaling and we identified a site of phosphorylation in the kinase domain of Her2/neu (tyrosine 877) that may directly regulate kinase activity. These proteomic findings may be of considerable importance in cancer treatment as Her2/neu is the target of two classes of drugs currently being used in breast cancer therapy. The identified novel signaling proteins may constitute additional drug target or may impact mechanisms of cancer cell resistance.

Our goals now are to demonstrate the biological function and importance of these proteomic findings and to apply proteomics to additional models of breast cancer, both in tissue culture and in mice.

Specifically, we will study:
(1) How phosphorylation of tyrosine 877 affects the activity and functioning of the Her2/neu protein.
(2) How several of these novel signaling proteins affect breast cancer cell response to drugs that target the Her2/neu protein.
(3) Apply SILAC and an alternate proteomics technique, iTRAQ, to breast cancer models to examine signaling proteins that affect tumor formation or response to cancer therapies.

Structures of EGFR kinase domain bound to small molecule kinase inhibitors

(A) Erlotinib–EGFR structure; (B) Lapatinib–EGFR structure; (A) HKI-272–EGFR structure
The panels show the entire EGFR kinase domain with inhibitor bound, revealing the active (A) and inactive (B and C) conformations of EGFR.

From: Bose R, Zhang X
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
Exp Cell Res 2009 Feb 15;315(4):649-58

 

Education

1991	B.S. (Zoology), B.A. (Chemistry), with Highest Distinction, University of Rhode Island, Kingston, RI
1998	Ph.D. (Pharmacology and Biochemistry), Cornell University, Graduate School of Medical Sciences, New York, NY
1999	M.D., Cornell University, Weill Medical College, New York, NY

Post-graduate Training

1999-2002	Internship and Residency in Internal Medicine, Washington University and Barnes-Jewish Hospital, St. Louis, MO
2002-2007	Fellowship in Medical Oncology, Department of Oncology, The Johns Hopkins Hospital, Baltimore, MD

Academic Positions

2007-present	Assistant Professor, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO
2007-present	Assistant Professor, Department of Cell Biology & Physiology, Washington University, St. Louis, MO

Board Certification

2002	Diplomate, American Board of Internal Medicine
2004	Diplomate in Medical Oncology

Honors & Awards

1989	Phi Beta Kappa Honor Society
1989	Phi Kappa Phi Honor Society
1991	University President's Award for Excellence in Zoology, University of Rhode Island
1993	Alpha Omega Alpha Medical Honor Society
1994	Lee Friedman Memorial Fellowship
1995, 1997	Award of Excellence, Vincent duVigneaud Symposium, Cornell University
1999, 2000	Caring Spirit Award, Barnes-Jewish Hospital
2001	Selected as Senior Resident to give Grand Rounds to Department of Medicine
2002	Resident's Teaching Award, Washington University
2006	AACR Scholar-In-Training Travel Award

Professional Societies

	American Society of Clinical Oncology
	American Association for Cancer Research
	American Association for the Advancement of Science
	American Society for Biochemistry and Molecular Biology
	American Society for Mass Spectrometry

• Updated: June 24, 2009
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