Architecture of the ErbB2 Molecule Leading to Breast Cancer

Institution: University of California, San Francisco
Investigator(s): Cara Marks, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2KB-0114 Award: $222,349
Award Type: New Investigator Awards
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (1996)
Breast cancer occurs when breast cells escape normal cell growth controls and grow without restriction. Proteins known as receptors play a crucial role in this process. In healthy tissue, receptors transmit a signal to the cell to grow when a smaller protein, called a growth factor or ligand, binds to the receptor. Ligand binding induces a change in the shape of the receptor, which causes receptors next to each other to connect. This change in shape and resulting connection between two receptors on the outside of a cell acts like a domino falling over and starts a chain reaction throughout the cell that causes the cell to grow. Thus, all that is needed to signal a cell to grow is a connection between two receptors.

Such a connection between receptors can occur spontaneously (without the growth factor binding to a receptor) if there are a lot of receptors on the surface of the cell, such that they frequently bump into each other. Thus, cells that have abnormally high levels of receptors can grow without receiving signals from growth factors. Indeed, the most common abnormality in human cancers involves receptor overproduction. Such overproduction has been reported in breast, prostate, ovarian, bladder and lung cancers. One particular family of receptors called the epidermal growth factor receptors (EGF/ErbB1-4) has been implicated more than any other. In approximately 30% of breast cancer patients, the ErbB2 receptor is overproduced, resulting in aggressive and uncontrolled growth of tumor cells.

In this project, we propose to examine the architectural features of the contact between ErbB2 receptors which leads to the abnormal growth characteristic of cancer. This will not only increase our understanding of the mechanism by which ErbB2 overproduction results in unregulated breast cell growth, but may also provide insights into the mechanism of action of other growth factor receptors. The long term goal of this proposal is to develop small molecules to arrest breast cancer growth by blocking interactions between ErbB2 biomolecules. To accomplish this goal the architectural features of ErbB2 must be determined. The approach described uses molecular biology, molecular modeling and x-ray crystallography to investigate the architectural details of ErbB2. The combined use of these techniques will allow us to overcome the hurdles frequently encountered with structure determination. Using this knowledge, drugs can be designed which specifically block this pathway and stop breast cancer tumor growth.

Final Report: Dr. Marks passed away in April, 1999 and the work on this grant was discontinued.