Yehenew M. Agazie , DVM, PhD

Professor

Organization:

West Virginia University School of Medicine

Department:

Biochemistry and Molecular Medicine

Classification:

Faculty

Member

Organization:

West Virginia University WVU Cancer Institute

Department:

WVU Cancer Institute Research Programs

Classification:

Faculty

• PhD, University of Saskatchewan, 1995

Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis.
Zhao H, Martin E, Matalkah F, Shah N, Ivanov AV, Ruppert JM, Lockman PR, Agazie YM.
Oncogene. 2019; 38(13): 2275-2290.
PMC6440805

SHP2 acts both upstream and downstream of multiple receptor tyrosine kinases to promote basal-like and triple-negative breast cancer.
Matalkah F, Martin E, Zhao H, Agazie YM.
Breast Cancer Res. 2016; 18(1): 2.
PMC4700603

Inhibition of SHP2 in basal-like and triple-negative breast cells induces basal-to-luminal transition, hormone dependency, and sensitivity to anti-hormone treatment.
Zhao H, Agazie YM.
BMC Cancer. 2015; 15(1): 1131.
PMC4359540

Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.
Farrugia MK, Sharma SB, Lin CC, McLaughlin SL, Vanderbilt DB, Ammer AG, Salkeni MA, Stoilov P, Agazie YM, Creighton CJ, Ruppert JM.
Cell Death Dis. 2015; 6: e1699.
PMC4385942

HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling.
Hartman ZR, Zhao H, Agazie YM.
Oncogene. 2013; 32(35): 4169-4180.
PMC3538112

The tyrosine phosphatase SHP2 regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration.
Hartman ZR, Schaller MD, Agazie YM.
Mol Cancer Res. 2013; 11(6): 651-664.
PMC3686999

The signaling and transformation potency of the overexpressed HER2 protein is dependent on the normally-expressed EGFR.
Zhou XD, Agazie YM.
Cell Signal. 2012; 24(1): 140-150.
PMC3205337

Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation.
Zhou XD, Agazie YM.
J Biol Chem. 2009; 284(18): 12226-12234.
PMC2673291

SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis.
Zhou XD, Coad JE, Ducatman BS, Agazie YM.
Histopathology. 2008; 53(4): 389-402.

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells.
Zhou XD, Agazie YM.
Cell Death Differ. 2008; 15(6): 988-996.

Mutation of Thr466 in SHP2 abolishes its phosphatase activity, but provides a new substrate-trapping mutant.
Merritt R, Hayman MJ, Agazie YM.
BBA-Mol Cell Res. 2006; 1763(1): 45-56.

Modulation of alpha-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3.
Burks J, Agazie YM.
Oncogene. 2006; 25(54): 7166-7179.

Breast Cancer

•Breast cancer
•Role of SHP2 in RTK and Wnt/β-catenin signaling pathways with particular emphasis to breast cancer

Description of Research

More often than not, cancer arises from dysregulation of normal cellular signaling and homeostasis. The receptor tyrosine kinase (RTK) and the Wnt/β-catenin signaling pathways are the most commonly dysregulated molecular abnormalities in breast cancer and other cancers. My lab focuses on the role of the Src homology phosphotyrosyl phosphatase 2 (SHP2) in these two signaling pathways with particular emphasis to breast cancer. The long-term goals are to define the molecular mechanism of SHP2 in mediating RTK and Wnt/b-catenin-driven signaling, to demonstrate its biological significance in breast cancer, to develop anti-SHP2 prodrugs, and determine its therapeutic value. Specific areas of focus are as outlined below.

Role of SHP2 in RTK Signaling and Tumorigenesis in Breast Cancer:

The expression of SHP2 is dysregulated in breast cancer, and plays essential roles in dysregulated signaling by multiple RTKs, including EGFR, HER2, MET, FGFR and IGF-1R. Recently, we have demonstrated that SHP2 also regulates the dysregulated expression of RTKs in both HER2-positive and triple-negative breast cancer. Furthermore, we and others have shown that SHP2 is required for tumorigenesis  and metastasis of mammary gland tumors in mice. However, the mechanism is poorly understood. In this project, we focus on identifying substrates for the SHP2 tyrosine phosphatase activity by a combination of substrate-trapping and mass spectroscopy techniques and characterizing them by site-directed mutagenesis and enzyme assays in vitro, and by ectopic expression in cells and determining effect on signaling and cancer cell phenotypes. We also employ various SHP2 inhibition approaches (e.g. shRNA, pharmacologic, and genetic) to determine effect on signaling, transformation, tumorigenesis and metastasis.

Role of SHP2 in Wnt/b-Catenin Signaling and Tumorigenesis in Breast Cancer:

Beta catenin is the major transducer of the Wnt signaling pathway. Recent studies show that beta catenin can also be activated by RTKs. Our findings further suggest that SHP2 is important for beta catenin stability in breast cancer cells and this leads to overexpression of EGFR and HER2. We are currently investigating the molecular mechanism of SHP2 in mediating beta catenin stability which in turn leads to RTK overexpression in breast cancer. We employ molecular, cellular and genetic approaches to address these questions.

Efficacy of SHP2 Targeting  in HER2-Positive and Triple-Negative Breast Cancer:

Overexpression of HER2 is the causes of HER2-positive breast cancer. Although current anti-HER2 therapies are effective initially, cancer cells often develop resistance, leading to disease recurrence which is virtually incurable. In case of triple-negative breast cancer (TNBC), no effective targeted therapy has been developed so far. We are currently studying if inhibition of SHP2 with small molecule prodrugs would be effective against naïve and therapy resistant forms of HER2-positive and TNBC. We use cellular and tumor models to test efficacy of anti-SHP2 compounds.