Date of Award
Fall 11-28-2023
Embargo Period
11-28-2028
Document Type
Dissertation - MUSC Only
Degree Name
Doctor of Philosophy (PhD)
Department
Biochemistry and Molecular Biology
College
College of Graduate Studies
First Advisor
Ozgur Sahin
Abstract
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women worldwide. It is a heterogeneous disease, and clinically classified into three subtypes: estrogen receptor-positive (ER+), HER2-positive (HER2+) and triple negative breast cancer (TNBC). Depending on the subtype, breast cancer patients can be treated with different targeted therapy and chemotherapy agents. However, a large fraction of patients exhibits disease recurrence, greatly reducing the clinical outcome. Here, three novel molecular targets that are overexpressed and associated with worse disease progression and therapy resistance in the most aggressive subtypes/subpopulations of breast cancer patients have been identified. Firstly, in ER+ breast cancer, constituting around 70% of all cases, it was found that the standard-of-care (SOC) therapies (e.g., tamoxifen, fulvestrant or palbociclib) used in clinics downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene, leading to BRCAness, activation of cAMP/ROS/DNA damage axis and cell death. On the other hand, PDE4D was shown to be overexpressed via EGFR-mediated c-Jun activation in SOC resistant tumors, associated with worse clinical outcome, and its therapeutic targeting in combination with SOC therapies in drug-resistant settings reinstates BRCAness, leading to drug sensitization. Secondly, in TNBCs, constituting around 10-15% of all cases, remodeling of tumor microenvironment via overexpression of the lysyl oxidase (LOX) enzyme was shown to drive chemoresistance. Targeting LOX leads to de-crosslinking of the extracellular matrix (ECM), increases drug penetration, and inhibits FAK-Src-mediated survival signaling, culminating in chemosensitization. Thirdly, the transforming acidic coiled-coil-containing protein 3 (TACC3) was identified as a novel centrosome amplification (CA)-directed dependency, driving cell growth by forming distinct functional interactomes with KIFC1 in mitosis or MBD2/HDAC2 complex in interphase during cell cycle progression. Targeting the spatiotemporal functions of TACC3 inhibits the growth of highly aggressive breast cancer tumors with CA. Overall, the work presented here contributes to a better understanding of the progression of highly aggressive breast cancers and provides novel and clinically translatable therapeutic strategies for breast cancer treatment.
Recommended Citation
Saatci, Ozge, "Targeted Multimodal Approaches to Treat Aggressive Breast Cancers via Therapeutic Inhibition of Key Vulnerabilities" (2023). MUSC Theses and Dissertations. 825.
https://medica-musc.researchcommons.org/theses/825
Rights
Copyright is held by the author. All rights reserved.