Date of Award

8-9-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Ritu Aneja

Second Advisor

Emilius Adrianus Maria Janssen

Third Advisor

Bingzhong Xue

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. High rates of metastasis and tumor recurrence in TNBC remain a clinical challenge contributing to the high mortality of TNBC. Metastasis is a multistep process that involves genomic, transcriptomic, and proteomic alterations. An in-depth understanding of the biological mechanisms underlying these metastasis-associated alterations is imperative for the development of precision therapies that target metastasis-specific markers in TNBC.

In this study, I used a multi-omics approach to identify global changes in mutational, gene, and protein expression profiles of metastatic breast cancer cells as they leave the primary site to seed proximal or distal sites. A similar mutational profile was observed between primary tumors and corresponding locoregional recurrences; MUC3A was identified as the most frequently mutated gene. Distinct gene expression profiles were observed between paired primary and metastatic tumors. Specifically, we found that three MammaPrint signature genes and MMP, FGF, and PDGFR family genes were upregulated in primary TNBCs with metastatic recurrence.

Using mass spectrometry and spatial imaging-based quantitative proteomic analysis, we assessed differences in the proteomic landscape of breast cancers with and without distant metastasis. We identified 49 differentially expressed proteins between serum samples from primary breast tumors with and without distant metastasis. Tumor microenvironment-wide comparisons revealed unique protein expression profiles associated with metastatic and non-metastatic TNBCs. Collectively, my findings indicate that (i) mutational signatures in primary breast tumors can serve as a proxy for the detection of disseminated cancer cells and locoregional recurrences, although additional variants may be acquired during disease progression; (ii) distinct gene and protein expression profiles exist between breast tumors with and without DM. These results suggest that metastatic cells undergo a biologically significant transcriptomic, genomic, and proteomic shift upon colonization of distant metastatic sites. This work expands our knowledge of molecular networks that have the potential to distinguish metastatic from non-metastatic disease and could guide the development of actionable therapeutic targets for metastatic TNBC.

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