Evaluating Phosphatidylinositide as Lipid Biomarkers for Hyperglycemia-related Triple-negative Breast Cancer Aggressiveness

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, marked by limited treatment options and poor patient outcomes. Clinical and epidemiological studies suggest that systemic metabolic conditions, particularly high blood glucose associated with Type 2 Diabetes, may worsen TNBC progression. However, there are no current biomarker for detecting TNBC, especially in hyperglycemic patients. This thesis investigates how elevated glucose levels influence TNBC behavior and whether lipid signaling molecules at the cell membrane, known as phosphatidylinositol lipids (PIs), can serve as biomarkers of disease progression. To address this, we combined functional assays that measure key cancer traits, including cell migration, attachment to the extracellular matrix (ECM), and cell accumulation, with lipidomic analyses of cell membranes under normal and high-glucose conditions. Our findings demonstrate that hyperglycemia enhances aggressive traits in TNBC cells, promoting increased movement and growth, but no effect on ECM attachment. In parallel, lipid profiling revealed alterations in PI molecules that regulate growth and survival pathways, with differences observed across cell models. These results highlight a direct connection between metabolic stress and cancer progression. By linking systemic metabolic dysregulation to cell signaling in TNBC, this work identifies PI4P, PI(4,5)P2 and PIP3 lipids as potential biomarkers and points toward new strategies for risk stratification and therapeutic intervention.