Project 1: LSR Alters Metabolic Signaling to Drive Aggressive Breast Cancer Behaviors

Partnership

This collaborative project fosters alliances between Dr. Keith Burridge, Professor, LCCC and Dr. Jodie Fleming, Assistant Professor, NCCU. This proposal initiated a unique collaboration between two research groups who have been investigating LSR in different contexts, Fleming studying lipid transport and extracellular matrix-cell interactions breast cancer, and Burridge investigating LSR in tight junctions and Rho GTPase signaling. They are the first to study LSR’s function in breast cancer, and the proposal may shed light on LSR as a link between obesity, race and breast cancer. This project has also promoted career development for Dr. Fleming through mentorship by Dr. Burridge. The PI’s contributions are evenly divided. Dr. Fleming is responsible for the coordination of project management and is responsible for submission of reports to the NIH. The PI’s have continued their quarterly meetings to discuss experimental design, data analysis, and manuscript preparation. Dr. Burridge has steered the design and analysis of the function of LSR in cell junctions and signaling to Rho GTPases (to-date) and Dr. Fleming has directed the microarray analysis, performed ChIP-seq experiments, and designed the metabolomics/lipidomics studies with Susan Sumner (RTI International), and is identifying LSR signaling pathways. The PI’s collaborators include Drs. Lee Graves, Laura Herring, Katherine Hoadley, Melissa Troester, and Charles Perou (LCCC). Each have provided clinical and/or bioinformatics/proteomics expertise during the execution of the project thus far. This partnership will continue to utilize UNC resources including the UNC Microarray, Proteomics, and Imaging Core Facilities. The goal of this proposal is to obtain sufficient data and publications to submit an R01, and the PI’s are continuing to strive towards this goal.

Cancer Disparity

African American (AA) women have lower incidence, but higher mortality rates when diagnosed with breast cancer. Biological differences in tumor subtypes, with greater prevalence of aggressive basal-like “triple-negative” breast cancers in AA women, explain some disparities. However, AA women also have higher mortality even within the more favorable outcome Luminal A breast cancers. The etiologic factors that lead to this disparity remain undefined. Escalating this disparity is the disease promoting effect of obesity, which is significantly higher in postmenopausal AA women. Although a high caloric diet is a major cause of obesity/metabolic syndrome, the specific genes that determine sensitivity to dietary obesity and their contribution to cancer phenotype and response to therapy remain elusive. Our preliminary data demonstrate that AA women have altered protein expression in both their normal breast tissue and tumor microenvironment. Thus, our primary objective is to identify the mechanisms involved in the development of aggressive, metastatic breast cancers in AA women, as a consequence of stromal effects at the site of the cancerous lesion. The observation that the normal breast tissue of AA women is enriched with proteins distinct from CA women, and that AA women are predisposed to develop basal-like breast cancer strongly suggests a biological link between race and cancer subtype.

Abstract

Recent studies revealed the lipolysis stimulated lipoprotein receptor (LSR) directly regulates hepatic post-prandial uptake of triacylglyceride-rich lipoproteins, is sensitive to high fat diets, and regulated by leptin. Our preliminary studies show LSR is overexpressed in breast tumors, directs aggressive cancer stem cell behaviors and chemotherapeutic resistance. Our pilot data suggest LSR levels are higher in AA tumors, mediates cellular lipid endocytosis and metabolic energy sources, and LSR is correlated with distant metastasis and poor survival. Together these results lead to our hypothesis that LSR alters lipid metabolism and cell signaling, thereby directing aggressive cell behaviors and chemotherapeutic resistance in breast cancer. Our goal is to identify disparity-associated molecular mechanisms that influence cancer
progression and clinical outcomes, with the ultimate goal of identifying novel targets for therapeutic development to reduce cancer disparities. This proposal addresses breast cancer disparities by studying the role of LSR in enhancing the aggressiveness of basal-like, luminal A, race- and obesity-associated breast cancers. By combining observational studies on differences in this pathway reflecting race, BMI, and breast cancer subtype with experimental studies to understand the role of this pathway in cellular phenotypes, this project should provide important and novel insight into the biological basis of racial disparities in breast cancer. Understanding mechanisms of that drive rapid tumor proliferation, metastasis, and recurrence are of fundamental importance to improving patient outcome for women suffering from aggressive breast cancers.

Co-Principal Investigators

Jodie Fleming, PhD NCCU	Keith Burridge, PhD UNC Lineberger