Date of Award

2022

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy in Biological Sciences (PhD)

Administrative Home Department

Department of Biological Sciences

Advisor 1

Xiaohu Tang

Committee Member 1

Ebenezer Tumban

Committee Member 2

Xiaoqing Tang

Committee Member 3

Tarun K. Dam

Abstract

Breast cancer is the first leading cause of cancer death in women globally. Particularly, triple-negative breast cancer (TNBC) is a highly aggressive subtype and lacks effective therapy. Metabolic deregulation is a hallmark of cancer and targeting metabolic vulnerabilities in cancer is an emerging strategy. Targeted cysteine therapy, implemented by blockage cysteine uptake and metabolism, can effectively kill some TNBC via rapid ferroptosis. However, not all TNBCs respond effectively in a similar manner. We investigated the underlying disparities of TNBC subgroups by transcriptomic analysis and identified that epigenetic sensitizers could optimize the targeted cysteine therapy applicable for all subgroups of TNBC. In addition, we observed that a residual cell population from the cysteine-dependent TNBC sustains resistance to multi-cycle erastin treatment, which most likely mimics tumor relapse in patients after therapy. To limit the risk of tumor recurrence and decipher the underlying mechanism, we enriched and established the erastin-resistant/recurrent TNBC cell models in-vitro. We found that such recurrent TNBC cells fail to grow at an anchorage-independent condition, implying loss of tumorigenicity. Recurrent TNBC displayed attenuated oncogenic signaling processes, such as K-Ras signaling. Knockout of CST4 by CRISPR/Cas9 revealed a novel signaling, which significantly suppressed K-Ras signaling and reduced tumorigenic potential. Our findings suggested that targeted cysteine therapy with optimizations could be an efficacious treatment for all TNBC with a low possibility of tumor formation.

Available for download on Friday, June 30, 2023

Share

COinS