Semester

Fall

Date of Graduation

2012

Document Type

Thesis

Degree Type

MS

College

School of Medicine

Department

Biochemistry

Committee Chair

Michael Schaller

Committee Co-Chair

Yehenew Agazie

Committee Member

Karen Martin

Committee Member

Scott Weed.

Abstract

Basal type/triple negative breast cancer (BTBC) represents a distinct tumor group that is characterized by an aggressive disease phenotype and poor clinical outcome. Patients with this subtype cannot benefit from the available anti-hormone and anti-HER2 targeted therapies (e.g. tamoxifen and herceptin). Therefore, characterizing potential therapeutic targets is urgently needed. We reasoned that the Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) could serve as a therapeutic target in BTBC, because of its critical regulation of epidermal growth factor receptor (EGFR) which is overexpressed in BTBC. Here, we demonstrated that SHP2 knockdown in BTBC cell lines suppressed cell proliferation, migration, and transformation. Furthermore, inhibition of SHP2 decreased the level of MMP9 in the conditioned media as shown by zymography and affected the invasive phenotype of BTBC cell lines in 3D matrigel. Most importantly, the results obtained from xenografts confirm that SHP2 plays an important role in the maintenance and progression of BTBC development and lung metastasis. Mechanistically, SHP2 depletion resulted in less-sustained EGF-induced Ras activation and decreased beta-catenin level, the latter of which resulted in an increase in p27 level. Taken together, these observations suggest that SHP2 plays essential roles in the development of BTBC and provide a rationale for targeting SHP2 in BTBC.

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