Author ORCID Identifier

https://orcid.org/0000-0003-0791-6882

Date of Graduation

5-2026

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Powel Brown, MD, PhD

Committee Member

Banu Arun, MD

Committee Member

Khandan Keyomarsi, PhD

Committee Member

Katharina Schlacher, PhD

Committee Member

Wendy Woodward, MD, PhD

Committee Member

Melinda Yates, PhD

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited targeted therapies. Despite lacking characteristic expression of nuclear or cell surface receptors like other breast cancer subtypes, there are molecular features shared by most TNBCs. These include TP53 mutations, occurring in 80-90% of TNBC, and BRCA mutations or other homologous recombination deficiency (HRD), found in about 60% of TNBC. Our goal was to identify new therapeutic options for TNBC through targeting these molecular features. A past screening effort in our lab identified KIF11 as capable of selectively inhibiting the growth of TP53-mutant breast cancer cells. We found that KIF11 inhibitors preferentially kill TP53-mutant as compared to TP53-wild-type breast cancer cells, and that KIF11 inhibitor treatment led to regression of TP53-mutant TNBC xenograft tumors. Furthermore, knockout of wild-type TP53 or overexpression of mutant-TP53 in a wild-type cell line caused increased mitotic dysfunction and cell death. Additionally, we designed and conducted a pharmacologic screen using BRCA1+/- paired cell lines to identify drugs that were more effective in BRCA1-deficient cells. This approach identified the STAT3 inhibitor Cucurbitacin I, the EGFR inhibitors WZ8040 and Canertinib, the PI3K inhibitor ZSTK474, and the GSK3Β inhibitors BIO and CHIR-99021 as having a greater growth inhibitory effect in BRCA1-deficient cells. Overall, the studies contained in this thesis have discovered new strategies for targeting common molecular alterations in the most aggressive form of breast cancer and could lead to new treatment options for TNBC.

Keywords

breast cancer, TNBC, targeted therapies, TP53, BRCA1, drug discovery

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