Elisha Martin

Date of Graduation

2016

Document Type

Thesis

Degree Type

MS

College

School of Medicine

Department

Biochemistry

Committee Chair

Yehenew M Agazie

Committee Co-Chair

Alexy Ivanov

Committee Member

Heimo Riedel

Committee Member

Micheal D Schaller

Abstract

Basel-like/ Triple Negative Breast Cancer (BTBC) are a subtype of Breast Cancer that are clinically characterized as an aggressive and highly metastatic disease phenotype and poor outcome for women who are diagnosed with this disease. Patients with BTBCs lack treatment options for target therapeutics that are available for other Breast Cancer subtypes (e.g. tamoxifen and herceptin) and have been shown to have a disproportional mortality rate in minority and in young woman of all races. The need to find and characterize a potential therapeutic target for BTBC is an exterimal important focus for many researcher laboratories. Src-homology phosphotyrosyl phosphatase 2 (SHP2) could potentially be therapeutic target for BTBC, for the reason it's an essential mediator of Receptor Tyrosine Kinases (RTKs),which are dysregulated in BTBC such as Epidermal Growth Factor Receptor (EGFR), c-Met, Fibroblast Growth Factor Receptor (FGFR) and ect. Here, we show that silencing of SHP2 in BTBC leads to a reduction in cell proliferation, transformation and a loss of a cancer stem cells phenotype. Furthermore, silencing of SHP2 in BTBC leads to a loss of basal and ligand stimulation signaling downstream to PI3k/AKT and MAPK/ERK1/2 pathways form RTK and RTK expression. We also show that silencing of SHP2 causes a reduction in beta-catenin proteins, loss of beta-catenin target gene expression and loss of nuclear localization. Silencing of beta-catenin in BTBC also showed a reduction in cell proliferation, transformation, loss of EGFR protein and mRNA expression along with a reduction in SHP2 protein levels. Taken together, these observations suggest that SHP2 is essential for RTK signaling, expression and beta-catenin proteins stability which is need for expression of RTKs in BTBC, showing that SHP2 can be a potential therapeutic target for BTBC treatment.

Download

Share

COinS