Date of Award

Spring 4-4-2025

Embargo Period

4-4-2030

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology

College

College of Graduate Studies

First Advisor

Peggi Angel

Second Advisor

Joesph Delaney

Third Advisor

Lauren Ball

Fourth Advisor

Richard Drake

Fifth Advisor

Laura Spruill

Abstract

Ductal carcinoma in situ (DCIS) is not considered lethal, but its progression to invasive breast cancer (IBC) and subsequent metastasis to regional areas significantly increases mortality risk. The transition to IBC is associated with a marked increase in many collagens. Collagen post-translational regulation, especially proline hydroxylation (HYP), is crucial in modulating collagen structure and function, but post-translationally modified collagen domains remain largely unmapped in breast cancer. We hypothesize that the regulation of the collagen proteome evolves from non-invasive to metastatic breast cancer. Here, extracellular matrix (ECM)-targeted mass spectrometry imaging followed by high-resolution mass-accuracy proteomics was used to assess ECM proteomic changes from non-invasive to metastatic breast cancer. A comparison of DCIS specimens from recurrent and non-recurrent patients revealed a trend of reduced HYP collagen peptide profiles in recurrent patients. A significant decrease in HYP collagen peptide intensities was observed in recurrence events compared to patient-matched primary DCIS specimens, as well as between Black and White women. Individual peptides could discriminate between recurrence and primary DCIS. Comparative studies between pure DCIS, mixed DCIS-IBC, and pure IBC revealed distinct peptide signatures dependent on pathology, with proximity to IBC regions influencing ECM signatures of DCIS in mixed DCIS-IBC cases. In a multi-proteomic study of metastatic triple-negative breast cancer, many ECM proteins and remodelers were differentially expressed between the primary tumors, metastatic lymph nodes (LN), and benign LN. Specific collagen types were increased within the primary tumor, while others were similarly expressed across sites. Discrete ECM peptides had differential intensities between metastatic and benign LN. This dissertation defines ECM proteomic signatures spanning non-invasive to metastatic breast cancer.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Thursday, April 04, 2030

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