Lipid raft composition in deregulated ERBB2 signaling
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Elevated amounts of the ERBB2 (HER2) oncogene growth receptor are clinically important in 25-30% of breast cancers. Yet, despite the availability of drugs (such as Herceptin) that specifically target ERBB2, the therapy may fail because we still do not fully understand the cellular components that control ERBB2 activity. For example, the immediate cell membrane micro-environment of ERBB2 is poorly understood, but would be expected to influence the receptor’s binding and signaling properties. Typically, the cell membrane is assumed to be inert and serves merely to hold ERBB2 in place. However, in reality the membrane surrounding ERBB2 is subdivided into a range of microenvironments, made up of lipids and embedded proteins that have been selectively recruited to specific locations. “Lipid rafts” are a subtype of cell membrane microdomain that generates a favorable packing environment for sterols and saturated fatty acids and some signaling proteins (such as H-Ras), based on the nature of their lipid anchors. Rafts have been shown to modulate both signal transduction and “trafficking” events (i.e., lateral translocations, internalization, and movements within cells). In addition, the composition of lipids of the plasma membrane is subject to changes by external factors (e.g. environmental and dietary fat) and is the most direct, but least understood, point of interaction between ERBB2 signaling and lipid metabolism. 
 
 
 
 
 
 
 
 In this project to study the role of lipid rafts on ERBB2 function, we are asking three basic questions: 
 
 
 
 
 
 -Do changes in saturated fatty acids in the plasma membrane alter the microenvironment of ERBB2 in a functionally relevant manner leading to among other things, Herceptin resistance?
 
 
 
 -Are saturated fatty acids and gangliosides linked functionally in a way that mediates this interplay between lipids and ERBB2? 
 
 
 
 -Can we classify subtypes of breast cancers based on the immediate microenvironment of ERBB2 and ultimately extend this knowledge to a better understanding of how diet or lipid profile altering drug regimens may influence the outcome of treatment? 
 
 
 
 
 
 
 
 
 
 To address these questions, we will first evaluate the functional linkage between lipid composition, ERBB2 control and Herceptin resistance in our test system using MCF-7 and BT474 breast cancer cell lines. Next, we will determine how changes in lipid profiles alter the microenvironment of ERBB2 and ERBB3, the primary dimerization partner for ERBB2 in signaling. Specifically, we will evaluate the impact of altered lipid compositions on the distribution of signaling partners that co-associate with ERBB2 and ERBB3 in lipid microdomains. 
 
 
 
 
 
 
 
 A better understanding of this understudied ERBB2-lipid raft interplay will provide mechanistic insights into the intrinsic control of cell growth, resistance to therapy, and how environmental/dietary factors may influence the course of the disease.