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Structure of HER2 receptor explains why Herceptin therapy is effective against breast cancer tumors with excess receptor

Discovery of the three-dimensional structure of the HER2 receptor, which is overexpressed in 20 to 30 percent of breast cancer cases, explains why antibody therapy with Herceptin is effective against those tumors, according to an article in the February 13th issue of Nature. The discovery also explains why overexpression of that receptor can result in cancer, whereas overexpression of other receptors in the same family does not result in tumors.

"Now we know exactly which building blocks of the Herceptin antibody interact with which building blocks of HER2," said Dan Leahy, Ph.D., a coauthor of the article. "When you understand the properties of receptors and antibodies in terms of their structural interaction, you can begin to explain their effects and use the information to design better drugs."

Herceptin, which was approved for use in the U.S. in 1998, kills cancer cells carrying excess HER2 receptor; however, the current study marks the first time anyone has understood precisely how the antagonist interacts physically with the receptor.

The findings also explain why the HER2 receptor behaves so differently from related growth factor receptors called HER1, HER3, and HER4, according to Leahy, whose team determined the structure of the HER3 receptor last summer. Although all four proteins are similar in amino acid sequence, only excess HER2 receptor leads to uncontrolled cell growth in both laboratory and human studies.

All of the receptors are transmembrane proteins, with part outside the cell and part inside the cell. Binding of the extracellular part causes HER receptors to form pairs, become fully active, and trigger events that result in cell division.

Comparison of HER receptor structures reveals that a few changes in amino acid sequence are the basis for the difference between HER2 and other HER receptors as stimulators of cell growth. Specifically, the HER2 receptor does not need to be opened through binding of a molecule before it can pair with another receptor. This is why the mere presence of extra receptors can cause cancer without the presence of ligands that bind to them, said Leahy.

"We can see now that it's unlikely any natural ligands for HER2 exist -- it just doesn't need one to work," added Leahy.

Led by Hyun-Soo Cho, Ph.D., the research team grew crystals of the extracellular part of the HER2 protein. After bombarding the crystals with radiation, the team interpreted the data to create the protein's structure. The team went through the same process with crystals of HER2 receptor bound to Herceptin antibody.

The researchers found that all of the HER receptors have extracellular regions made up of four structurally distinct sequences, or domains. HER 1 and HER3 receptors have a bracelet-shaped loop that connects the second and fourth domains. However, HER2 has a tight connection between the first and third domains, which prevents formation of the bracelet-shaped loop and opens the fourth domain for potential binding with Herceptin antibody.



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