Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive subtype of cancer with poor prognosis due to high metastatic potential and lack of targeted therapies. Normal epithelial cells express the microRNA-200c (miR-200c), a potent suppressor of epithelial-to-mesenchymal transition (EMT). However, miR-200c is silenced or lost in TNBC, allowing a de-differentiated, non-epithelial phenotype and aberrant expression of genes conferring invasive and chemoresistant characteristics. Recent literature has demonstrated that EMT promotes altered tumor cell metabolism, creating novel vulnerabilities that can be exploited therapeutically. In addition to driving global metabolic changes, miR-200c-induced reversal of EMT alters key cholesterol metabolism genes that support the uptake of dietary cholesterol from the bloodstream. Intracellular cholesterol homeostasis is critical for cell survival and is carefully regulated, but how these homeostatic mechanisms adapt during tumor progression is poorly understood. Based on preliminary data, I hypothesize that TNBCs depend on exogenous cholesterol uptake and availability to maintain cell viability and an invasive phenotype. This work aims to identify novel cholesterol-related targets in breast cancer and delineate mechanisms regulating cholesterol homeostasis in normal and cancer physiology.Restoration of miR-200c in TNBC leads to alteration of the cholesterol uptake components low- and very-low-density-lipoprotein receptors LDLR and VLDLR, through direct and indirect mechanisms previously unexplored in cancer. miR-200c further inhibits Niemann-Pick Type C (NPC1), a lysosomal protein necessary for utilization of exogenous cholesterol. Interestingly, expression of NPC1 in TNBC correlates with a unique inability of cells to proliferate in the absence of exogenous LDL supply, suggesting defects in de novo cholesterol biosynthesis. Further, NPC1 inhibition leads to cell death in TNBC but not more epithelial-like breast cancers. Whether this cell death is due to disruption in critical cholesterol supply or due to defective lysosome dysfunction is currently being investigated. Overall, this work suggests a role of NPC1 in cancer cell metastasis that has not been previously explored, and identifies cholesterol uptake as a targetable dependency in TNBC.
Obesity, Cholesterol Metabolism, and Breast Cancer Pathogenesis
