BioWorld International Correspondent

LONDON - The search is on for broken and rearranged chromosomes in common cancers such as those of the bowel and breast. Such rearrangements have long been associated with leukemias, but a new discovery now shows that they may be more important in common cancers than scientists had realized.

Research funded by Cancer Research UK, the UK's largest cancer research charity, has shown that broken and rejoined chromosomes - known as chromosome translocations - can occur repeatedly in the same place in cell lines from both breast and pancreatic cancers.

The work was carried out by researchers at the Hutchison/Medical Research Council Research Centre at the University of Cambridge in Cambridge, UK, in collaboration with a team at the Institut Paoli-Calmettes in Marseilles, France.

Paul Edwards, senior lecturer in pathology at the University of Cambridge, who led the UK team, told BioWorld International, "This study is a landmark because this is the first time that anyone has shown that such chromosome translocations occur in common cancers."

The discovery is all the more convincing, Edwards said, because the break in the chromosomes occurs in the middle of a gene called NRG1, which encodes a protein called heregulin that already was known to play an important role in epithelial cancers such as breast cancers.

He predicts that scrutiny of the genes affected by similar translocations will provide researchers a productive new way of identifying genes that play important roles in common cancers.

An account of the study appears in the August issue of Genes, Chromosomes and Cancer. The title of the paper is "A Recurrent Chromosome Translocation Breakpoint in Breast and Pancreatic Cell Lines Targets the Neuregulin/NRG1 Gene."

Chromosome translocations occur when chromosomes break and the cell tries to repair them. Sometimes the repair machinery joins up the wrong fragments. Depending on whether the break is in the middle of a gene or not, that can lead to the creation of new genes or the loss of others.

In leukemias, researchers have exploited such genetic defects in the search for new treatments, arguing that therapies directed at the bizarre "fusion protein" that results should be highly specific because this molecule is present only in the leukemic cells. In chronic myeloid leukemia, for example, two genes called BCR and Abl are fused together by a chromosomal translocation. The resulting protein has a tyrosine kinase function, which is inhibited by the anti-leukemia drug Gleevec.

Edwards was interested to find out if such chromosome translocations were important in more common cancers. About 10 years ago, he began to collaborate with researchers in Cambridge who were working on fluorescent labeling of chromosomes. "This technique allows you to stain chromosomes with fluorescent DNA markers to find out where the breaks and joins have been," he said. "Once the complete map of the human genome became available, we were able to see exactly what was going on."

Of 43 tumor cell lines they examined, the group found seven with chromosomal translocations affecting the heregulin protein. "This was a very interesting finding," Edwards said, "because it was already known that heregulin binds to a group of surface receptors including one called HER2, also known as erbb2, and that about 20 percent of breast cancers have high expression of the HER2/erbb2 protein." Furthermore, he added, there is already a monoclonal antibody therapy for breast cancer, called Herceptin, which binds to the HER2/erbb2 receptor.

"It seems likely," Edwards continued, "that we have found a separate group of breast cancers that have abnormal production of heregulin switched on, rather than having high expression of the receptor for heregulin."

The team now wants to find out how frequently the translocation they have identified occurs in breast and pancreatic cancers, and whether it occurs in other common cancers, too. "We want to know if the tumors with this translocation behave differently to tumors that do not have this chromosomal change," Edwards said. "We need to know more about the biochemistry of these tumors, to find out if they are just producing very large amounts of normal heregulin, or if they are producing a modified heregulin."

He believes that heregulin could prove a good target for monoclonal antibody therapy. "Ultimately we hope to identify hundreds if not thousands of chromosomal changes in common cancers, and find common events where the same bit of genome has been targeted on many occasions, leading to cancer. Our dream would be to find a chromosomal change that is present in, say, 30 percent of bowel cancers and 30 percent of breast cancers, which could provide us with a truly cancer-specific drug target," Edwards concluded.

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