Fluid Force Alterations in Cultured Mammary Epithelial and Breast Cancer Cells: Applications in Breast Cancer Diagnosis
Abstract
Metastatic progression of breast cancer is characterized by mechanical interactions between tumor cells and various microenvironments, including exposure to fluid flow. Complementing genomic and molecular signaling studies with fluid mechanics holds the promise of providing in-depth knowledge into how these interactions affect the ability of tumor cells to undergo metastasis, and identification of novel biomarkers that can potentially facilitate breast cancer diagnosis and treatment.
In this thesis, a bioreactor system was used to expose cultured mammary epithelial and breast cancer cells to fluid shear stress in the physiological range of those experienced in the vascular microenvironment. Genome-wide expression analysis revealed an effect of fluid flow on gene expression patterns and cellular processes involved in metastasis such as EMT, cell migration and adhesion. In addition, TGF-β signaling activity was significantly enriched and several genes belonging to this pathway were overexpressed upon flow exposure.
Subsequently, we sought to identify novel flow-responsive biomarkers for breast cancer. For this purpose, bioinformatics and network biology approaches were used to reveal significant enrichment of biological processes involved in metastatic progression. Expression levels of differentially expressed genes were evaluated in clinical expression datasets, and 14 genes were identified as potential biomarkers. Relative expression levels of seven of these biomarkers were quantified in breast cancer patients and healthy volunteers. Five biomarkers passed the threshold for statistical significance and were overexpressed in more than 80% of patients presenting with basal and HER2-enriched breast cancers, which are the most aggressive subtypes of breast cancer.
To our knowledge, the studies presented herein are the first of their kind to demonstrate that using an in vitro model to simulate exposure of cells to fluid shear stresses allows for identification of biomarkers for breast cancer. Using this system to study cellular events involved in other types of cancers may lead to new diagnostic and therapeutic approaches for metastatic cancer progression.
Description
Keywords
Bioinformatics, Biology--Cell, Biology--Molecular, Oncology, Engineering--Biomedical
Citation
Fuh, K. F. (2016). Fluid Force Alterations in Cultured Mammary Epithelial and Breast Cancer Cells: Applications in Breast Cancer Diagnosis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26197