ErbB2 research may give key to cancer growth

Researchers at the CRC for Cellular Growth Factors have determined the structure of ErbB2, providing an important clue in how the molecule may contribute to the uncontrolled growth of cancer cells.

The structure is being published today in Molecular Cell by the scientists, who come from CSIRO Health Sciences and Nutrition, the Ludwig Institute for Cancer Research and the Walter and Eliza Hall Institute of Medical Research (WEHI).

According to Tim Adams, ErbB2 is a member of the epidermal growth factor (EGF) receptor family. Other members of the family include the EGF receptor, also known as ErbB1, as well as ErbB3 and ErbB4. The structure of the EGF receptor in complex with its ligand transforming growth factor alpha (TGF alpha) was determined last year by the same group.

ErbB2, which is also known as Her2, has been associated with a range of cancers, in particular with breast cancers, where 30 per cent of tumours express ErbB2 and the receptor is the target for breast cancer drug Herceptin.

Unusually, ErbB2 is the only member of the family that does not require a growth hormone or ligand to activate it, a fact that has puzzled researchers. Instead it forms heterodimeric complexes with the other ErbB receptors, activating a signalling cascade via the receptors' tyrosine kinase domains which leads to cell division and differentiation.

"ErbB2 gets recruited into complexes with ErbB1, ErbB3 or ErbB4 when they have bound to their respective ligand," said CSIRO scientist Tim Adams, one of the authors of the paper. "But when you have a lot of ErbB2 it tends to form a dimer with itself, which causes problems."

Until now, the researchers had no idea how ErbB2 could self-activate in this way. But the three-dimensional structure has helped to explain it. According to WEHI structural biologist Tom Garrett, the receptor is already folded into the active state, ready to interact with its partners when they become available.

"ErbB2 is like a gun that is pre-cocked. Binding to other members of the same family of proteins pulls the trigger which sets off cell division," he said.

Now that the researchers have a good idea of the structure of ErbB2 and the domains that might be important in forming complexes, they are planning to use the structure to design antagonists capable of blocking the interaction, Adams said.

"The ultimate objective is to design precisely targeted drugs that sabotage the operation of this receptor family and thus weaken cancer cells which are dependent on this system. Now that we know how ErbB2 works we are aiming to block this action and stop the signal for cell growth," he said.

A range of approaches can be tried, Adams said, including antibodies, peptides and small molecule drugs. The CRC has filed for patents on the use of the three-dimensional structures as templates for developing antagonists.

In addition, the researchers would like to fill in the gaps in their knowledge of the structures. "We would love to see what ErbB2 looks like in the presence of the other receptors," said Adams.