Futurity.org ? Protein 'jailbreak' prolongs breast cancer

Senior author Rachel Altura says the research suggests a clear strategy?to keep survivin in the nucleus?and two leads to pursue it, both of which she has already begun working on with collaborators in academia and in the pharmaceutical industry. (Credit: iStockphoto)

BROWN (US) ? Researchers have traced the molecular interactions that allow a protein to escape the nucleus of a breast cancer cell and extend its life.

The? findings may help develop better therapies and prognostics for the disease, researchers say.

If the fight against breast cancer were a criminal investigation, then the proteins survivin, HDAC6, CBP, and CRM1 would be among the chief suspects. A new study published in the Journal of Biological Chemistry reveals the key moment for keeping cancer cells alive is the survivin?s jailbreak from the nucleus, aided and abetted by the other proteins.

The study highlights that a protein?s location in a cell affects its impact on disease and offers clear new leads for the investigation.

All four proteins were already under suspicion. Scientists, for example, have already tried to assess what levels of HDAC6 in patients with estrogen-receptor positive breast cancer may mean for their prognosis, but the results have been inconclusive.

The new research suggests that measuring overall levels may not be enough, says the study?s senior author Rachel Altura, associate professor of pediatrics at Brown University and a pediatric oncologist at Hasbro Children?s Hospital. ?We need to look not only at the levels, but also where is it in the cell.?

Altura?s emphasis on location comes from what her research team found as they tracked and tweaked the comings and goings of survivin in cells. Inside the nucleus, survivin is no problem. Outside the nucleus, but within the cell, it can prevent normal cell death, allowing cancer cells to persist.

In previous work, Altura and her collaborators established that under normal circumstances, CBP chemically regulates survivin, a process called acetylation, and keeps it in the nucleus. The question in the new work was how survivin gets out.

In a series of experiments, the researchers observed that in human and mouse breast cancer cells, HDAC6 gathers at the boundary between the nucleus and the rest of the cell, becomes activated by CBP, then binds survivin and undoes its acetylation. This deacetylation allows survivin to then be shuttled out of the nucleus by CRM1.

In the classic jailbreak, CBP is a corrupt guard who looks the other way as HDAC6, the shovel, is smuggled in. The final accomplice, CRM1, is the tunnel with a getaway car on the other end.

Working new leads

Altura says the research suggests a clear strategy?to keep survivin in the nucleus?and two leads to pursue it, both of which she has already begun working on with collaborators in academia and in the pharmaceutical industry.

One idea is to inhibit HDAC6 in an attempt to prevent it from misregulating the acetylation of survivin. While general HDAC inhibitors are in clinical trials, Altura is optimistic that blocking just HDAC6, using specific inhibitors developed by a colleague in Japan, would have fewer complications.

?You always have to worry about all the things you don?t know that you are targeting,?she says. ?If we can target HDAC6, we can maybe block survivin from coming out of the nucleus and maintain it in its good state.?

The other strategy is to block CRM1, an idea Altura is pursuing with a pharmaceutical company in breast cancer cells in the lab. Preliminary experiments look promising in keeping survivin inside the nucleus and making cancer cells more susceptible to dying.

Brown graduate student Matthew Riolo is lead author of the study that was funded by the National Institutes of Health?s Center for Research Resources.

More news from Brown University: http://news.brown.edu

Source: http://www.futurity.org/health-medicine/protein-jailbreak-prolongs-breast-cancer/

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