Date of Award
Spring 2026
Abstract
Triple negative breast cancer (TNBC) and high grade serous ovarian cancer (HGSOC) are highly deadly and common female diseases with poor prognoses and low survival rates. Current standards of care, including cytoreductive surgery and adjuvant chemotherapy, are not effective against advanced disease states in which tumors have metastasized and are often chemoresistant. This necessitates novel and more effective treatment strategies for metastatic TNBC and HGSOC patients. The oncogene STAT3 (Signal Transducer and Activator of Transcription 3) is an attractive drug target because STAT3 is constitutively active in both cancers and transcriptionally upregulates cell survival, suppresses apoptosis, and augments metastasis through increased cell migration, invasion, and mesothelial clearance. Herein, I evaluated nine previously identified candidate STAT3 inhibitors: defactinib, fostamatinib, LY2090314, sorafenib, regorafenib, AZA1, belumosudil, piceatannol, and indirubin. We hypothesized that the identified drugs would inhibit STAT3, thus repressing downstream STAT3 promotion of cell survival and metastasis in TNBC and HGSOC. Preliminary testing of candidate STAT3 inhibitors was primarily completed in the TNBC cell line, MDA-MB-231, and included additional testing in the OVCAR8 HGSOC cell line. Preliminary testing aimed to confirm STAT3 inhibition, assess drug cytotoxicity, and begin determining drug effects on TNBC and HGSOC metastasis. Several candidate STAT3 inhibitors efficiently reduced STAT3 phosphorylation by western blot, and decreased TNBC and HGSOC 2D and 3D viability and metastasis. From the preliminary tests, fostamatinib was identified as the most promising candidate and an in-depth analysis of fostamatinib was pursued. Fostamatinib is a Spleen Tyrosine Kinase inhibitor (SYK) that is FDA approved for the treatment of immune thrombocytopenia. We hypothesized that fostamatinib induced STAT3 inhibition through a SYK dependent mechanism and that inhibition of STAT3 by fostamatinib would induce apoptosis and decrease cell viability, chemoresistance, migration, invasion, and mesothelial clearance of TNBC and HGSOC cell lines. To delineate the fostamatinib mechanism of STAT3 inhibition, I performed mechanistic studies by western blot and transfection with targeted small interfering RNA. Because STAT3 is known to promote cell survival, I assessed 2D and 3D viability of several fostamatinib treated human breast and ovarian cancer cell lines. Given that platinum chemoresistance is a major treatment barrier for TNBC and HGSOC patients, I also assessed the cytotoxicity of fostamatinib and cisplatin combination treatments against cisplatin resistant HGSOC cells. Finally, the role of STAT3 in TNBC and HGSOC metastasis is well established. Therefore, I evaluated fostamatinib in multiple TNBC and HGSOC 2D and 3D metastasis models. Thus far, my results confirmed fostamatinib induced STAT3 inhibition but suggested that STAT3 is inhibited through upstream targeting of JAK2 rather than through a SYK dependent mechanism. Fostamatinib also efficiently reduced viability of 2D and 3D TNBC and HGSOC cell lines, and abrogated 2D and 3D TNBC and HGSOC cell motility. Taken together, my results indicate that fostamatinib could be used as a new therapy to inhibit STAT3 and treat metastatic breast or ovarian cancer.
Document Type
Master's Thesis
First Advisor
Sarah R Walker
Second Advisor
Paul C Tsang
Third Advisor
Vicki Jeffers
Department or Program
Biochemistry
Degree Name
Master of Science
Recommended Citation
Veronneau, Katherine Elaine, "Targeting STAT3 in breast and ovarian cancer" (2026). Master's Theses and Capstones. 2082.
https://scholars.unh.edu/thesis/2082