January 18, 2008

A ‘Neu’ interaction in breast cancer explored

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(photo by Neil Brake)

A ‘Neu’ interaction in breast cancer explored

When it comes to cancer, the protein EphA2 has a split personality.

In some circumstances, it seems to promote cancer growth and metastasis (oncogene), while at other times it appears to inhibit tumor growth (tumor suppressor).

In the January issue of The Journal of Clinical Investigation, Jin Chen, M.D., Ph.D., and colleagues provide evidence that EphA2's role depends on the cellular and genetic context of the tumor — in particular, the presence of another famous human breast cancer gene, Her2.

EphA2 is a cell surface receptor commonly over-expressed in aggressive breast cancer, and its expression correlates with poor prognosis. However, previous studies have yielded conflicting results on the role of this receptor.

“This study was done mainly to look at what sort of role EphA2 plays in tumor cells,” said Chen, associate professor of Medicine, Cancer Biology, and Cell & Developmental Biology. “In the field, the controversy is whether this is an oncogene or a tumor suppressor.”

Chen and colleagues examined EphA2 deficiency in two different mouse models that recapitulate the stages of human breast cancer formation and progression.

In one model, mice over-express a cancer-promoting gene known as Neu — the rodent version of the human Her2 gene, whose expression in breast cancer is used to determine whether the patient will respond to the drug Herceptin. In the other mouse model, mice express a viral oncogene, PyV-mT.

The researchers eliminated EphA2 expression either by gene deletion in mice or with an antibody that recognizes and causes the degradation of the receptor. They found that EphA2 deficiency in mice expressing Neu impaired both tumor initiation and progression. Neu-expressing mice showed reduced tumor volume and lung metastasis when EphA2 was eliminated. EphA2 deficiency had no noticeable effect on tumor progression in the other mouse model.

In cultured mouse and human breast cancer cells, Chen found that EphA2 interacts with Neu, and this complex activates cell signaling pathways that promote cell growth and motility. The results suggest that EphA2 cooperates with Neu to promote tumor progression and could be a potentially useful target for Neu (Her2)-dependent tumors. Antibodies to EphA2 receptor are being developed by a pharmaceutical company.

Chen had previously found that EphA2 not only played a role in tumor cell growth, but also in angiogenesis, the formation of the small blood vessels required for tumor progression. This could provide a two-pronged attack on breast tumors.

While some may argue that this lack of specificity would make EphA2 an undesirable drug target, Chen thinks otherwise. “It seems to me that this is an advantage rather than disadvantage. By targeting one thing (EphA2 receptor), you can inhibit angiogenesis and tumor cell growth.”

“We think (EphA2) is a good therapeutic target…particularly as combination therapy with an inhibitor of (Her2), like Herceptin,” said Chen.

Chen is currently studying whether cells resistant to Herceptin might benefit from treatment with EphA2-targeted treatments. “We are finding that, in some of the cells that are resistant to Herceptin, if we treat with antibody to EphA2, they become more sensitive to Herceptin. So this is a future direction, to see whether combination therapy is more effective.”