Date of Award

Spring 3-21-2023

Embargo Period

5-5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Peggi M. Angel

Second Advisor

Amy D. Bradshaw

Third Advisor

Richard R. Drake

Fourth Advisor

Anand S. Mehta

Fifth Advisor

Michael C. Ostrowski

Abstract

Breast cancer is the most diagnosed cancer among women worldwide and the incidence rates are rising annually. The rates of metastatic breast cancer are projected to increase by 54.3% from 2015 to 2030. Breast stroma plays a significant role in breast cancer risk and progression yet remains poorly understood. In breast stroma, regulation of post-translational modifications (PMTs) is representative of the health state of the local microenvironment. Two abundant PTMs in the extracellular matrix include hydroxylation of prolines (HYP) and N-glycosylation in collagen and non-collagen proteins, respectively. Here, mass spectrometry imaging (MSI) was used to investigate the spatial N-glycomic and collagen proteomic patterns in normal breast microenvironments from women at high risk for breast cancer. N-glycomic analysis of normal breast tissue revealed that specific fucosylated and high-mannose N-glycan structures had intensity patterns and histological distributions in breast tissue that were dependent on body mass index (BMI), breast densities, and genetic-ancestry. Normal breast tissue from black women with heterogeneously dense breast followed fucosylated and high-mannose patterns as seen in primary breast cancer. Application of a linear regression model showed that lifestyle factors differentially associated with fucosylated and high-mannose N-glycans based on ancestry. Further, collagen proteomic analysis from normal breast tissue demonstrated that collagen peptides may be influenced by cell specific signaling within the local microenvironment. Post-menopausal women on aromatase inhibitors and sulindac, a non-steroidal anti-inflammatory drug, showed that changes in mammographic density associated with specific collagen peptide alterations including HYP-modified peptides. Analysis of histology-directed MSI using tumor suppressor PTEN revealed heterogeneous PTEN staining patterns associate with HYP-modified collagen peptides suggestive of potential roles in stromal protein regulation. Overall, the studies presented in this dissertation are the first to detail the N-glycan and collagen peptide spatial distributions on the normal breast microenvironment. Our findings demonstrate the relation between molecular PTM profiles and varying breast cancer risk factors. We anticipate that these studies will give rise to future studies looking at potential biomarkers in the breast NME towards breast cancer control and prevention.

Rights

Copyright is held by the author. All rights reserved.

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