Utilizing GSK3beta and integrin inhibitors to target STAT3 activity in triple negative breast cancer
Date of Award
Spring 2024
Project Type
Thesis
Program or Major
Biochemistry
Degree Name
Master of Science
First Advisor
Sarah R Walker
Second Advisor
Nathan Oldenhuis
Third Advisor
David Plachetzki
Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer associated with poor prognosis and characterized by increased rates of proliferation and metastasis. TNBC gets its name due to the lack of the three receptors commonly found in other breast cancer types: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Breast tumors expressing these receptors can be treated with hormonal therapies, but TNBC tumors will not respond to such treatments and are therefore more difficult to treat. To circumvent this, targeted therapies that inhibit proliferation and migration are of great research and clinical interest. In TNBC, the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively active and promotes proliferation and migration. We hypothesized that by therapeutically targeting STAT3, the viability and migratory ability of TNBC cells would decrease. Using the Broad Institute’s online program CLUE to analyze a gene signature of STAT3 inhibition, we identified two compounds, TWS-119 and Cilengitide, that had high similarity to STAT3 inhibition and known functions relevant to proliferation and migration. TWS-119 inhibits the kinase GSK3beta and Cilengitide is an integrin inhibitor, and both proteins are known to play a role in proliferation and migration. We found that TWS-119 and Cilengitide synergistically decrease the viability of MDA-MB-231, Hs587T, and MDA-MB-468 TNBC cells and that TWS-119 reduces migratory ability. We next asked how GSK3beta, integrins, and STAT3 are related in a cell signaling context as they have not been previously studied together in TNBC. Through mechanistic studies, we determined that TWS-119 and Cilengitide in combination decreases cytoplasmic pY-STAT3, Cilengitide decreases nuclear pY-STAT3, and that the drug combination inhibits STAT3 activity. By utilizing TWS-119 and Cilengitide, we were able to show that targeting GSK3beta, integrins, and STAT3 is a viable option for treating TNBC and propose a novel cell signaling mechanism.
Recommended Citation
Pratt, Emily Anne, "Utilizing GSK3beta and integrin inhibitors to target STAT3 activity in triple negative breast cancer" (2024). Master's Theses and Capstones. 1844.
https://scholars.unh.edu/thesis/1844