Modeling the Heterogeneity and Targeting the Resistant Mechanism of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of human disease. This thesis investigates the role of MYC, a common TNBC deregulated oncogene, in TNBC microenvironment complexities, with a focus on oncogenic transformation of MYC driven therapeutic resistance as well as the functional consequences of targeting MYC in TNBC. Such understanding potentiates a critical need in the field to identify effective targeted therapy for TNBC and establishes a foundation for translating preclinical findings into effective human clinical trials. The studies are organized in the following outline; In Chapter 1, I delve into the background of MYC and its role in therapeutic resistance in TNBC. In Chapter 2 research, which has been accepted for publication in Nature Communications, we developed a novel heterogeneous TNBC murine model (Myc;Ptenfl) by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. In Chapter 3 research, which is in preparation for submission for publication, I use this TNBC preclinical model to address how oncogenic transformation of MYC can support therapeutic resistance in TNBC. Finally, in Chapter 4, I connect all the threads and provide thoughts on future directions of this research.