Thesis Format
Monograph
Degree
Master of Science
Program
Anatomy and Cell Biology
Supervisor
Allan, Alison L.
Abstract
Breast cancer is a leading cause of cancer diagnosis and death in Canadian women, with >90% of deaths caused by metastasis. The current study explores how hypoxia affects cancer aggressiveness and metastatic potential across breast cancer cell lines representing different molecular subtypes and those that metastasize to different organs. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS), comparison of normoxic and hypoxic proteomes of different breast cancer cell lines revealed changes to pro-survival and metastatic mechanisms contributing to subtype-associated aggressiveness. We also identified that extracellular exosomes and associated integrins are significantly upregulated components of the hypoxia response, suggesting their role in metastasis, especially to bone. Additionally, 8 clinically significant hypoxia-enriched proteins were identified specific to triple negative disease outcomes. Overall, hypoxia mediated subtype-specific aggressiveness and metastatic behavior, potentially via extracellular exosomes. This research offers insights into subtype-specific differences and identifies potential therapeutic opportunities to mitigate breast cancer metastasis in the future.
Summary for Lay Audience
Breast cancer is a major health concern for women worldwide, often leading to fatal outcomes when it spreads beyond its original site via a process called metastasis. As tumors naturally grow, the cancer cells located in the middle of the tumor are not always able to access the blood circulation, resulting in a lack of oxygen. Breast cancers respond differently to factors in their environment, especially to low oxygen levels (hypoxia), which can make them more aggressive and prone to spreading. The current study sought to determine how hypoxia affects the behavior of different types of breast cancer and what factors contribute to metastasis. Six different breast cell line models representing normal breast cells and different kinds of breast cancer were exposed to either normal oxygen levels or low oxygen conditions that mimic the hypoxic tumor environment. Using a high sensitivity machine called a mass spectrometer we analyzed the proteins within these cells and discovered significant changes in their activity and behavior when exposed to hypoxia. Specifically, we found that hypoxia activates pathways that help breast cancer cells survive, multiply and spread, making them more dangerous. Interestingly, these effects varied across different breast cancer types and were representative of respective clinical risks experienced by breast cancer patients. Moreover, our research highlighted the importance of extracellular exosomes, tiny packages released by cancer cells that can modify other organ tissues. In doing so, exosomes create favorable environments for successful cancer spread and growth in distant organs. We identified proteins activated by hypoxia called integrins that contribute to selective modification of organs, specifically bone. By releasing hypoxic exosomes with specific integrins, breast cancers may selectively modify organs to guide their spread. Additionally, our analyses revealed 9 unique hypoxic proteins that contribute to breast cancer survival and metastasis. We propose these proteins as potential therapeutic targets to limit the cancer aggressiveness produced by hypoxia. These findings pave the way for developing therapies against breast cancer to limit metastasis, with the ultimate goal of improving patient outcomes in the future.
Recommended Citation
Susman, David P., "Understanding How Hypoxia Alters the Breast Cancer Proteome in the Context of Molecular Subtypes and Metastatic Organotropism" (2024). Electronic Thesis and Dissertation Repository. 10107.
https://ir.lib.uwo.ca/etd/10107