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What do real estate and the cancerous protein survivin have in common? The answer, according to a recent study by University researchers, is location, location, location. Just as location is a key factor in determining the value of a property for homeowners, it is a key factor in determining the value of survivin ­- a protein involved in breast cancer progression - to cancer cells.

While previous studies have focused on the overexpression of proteins linked to tumor development, a study by a team of Brown researchers published last month in the Journal of Biological Chemistry is the first to suggest that location, rather than quantity, of a protein can influence cancer cell survival mechanisms. 

When survivin is exported from a cell's nucleus - the DNA-containing core ­- to the outer fluid region of the cell, known as the cytosol, it makes cancer cells immune to classic treatments, such as chemotherapy and radiation. But contained in the nucleus, it is unable to accomplish this function. 

"Nuclear levels are more tightly controlled by other factors and perhaps have more checks and balances to regulate them," said Rachel Altura, principal investigator and associate professor of pediatrics at Alpert Medical School. But outside the nucleus, survivin prevents cell death, thus allowing breast cancer cell proliferation.

"Survivin is truly unique in this regard," said lead author Matthew Riolo GS. "Our research helps point out that maybe expression level is not enough when predicting cancer outcome." 

The study details the mechanism of survivin's export from the nucleus and examined cancer cells from both mice and humans. When survivin contains an acetyl group, it is restricted to the nucleus. The protein HDAC6 removes this acetyl group, allowing survivin to escape to the cytosol. HDAC6 is regulated by the protein CBP, which is in turn regulated by estrogen levels. 

The study is "a very timely one of immediate interest to a wide audience," said Ed Seto, senior member of the H. Lee Moffitt Cancer Center and Research Institute who was not involved in the project. 

The findings of the research can implicate new molecular targets for potential breast cancer therapies. Currently, Altura and colleagues are collaborating with a biopharmaceutical company, Karyopharm Therapeutics, to develop novel drug therapies that prevent survivin from relocating to the cytosol. The strategy is to inhibit broad classes of molecules that mobilize survivin, thus confining it to the nucleus, where it seems to be innocuous. 

But in inhibiting a wide range of molecules, "there is always a concern that inhibiting a protein involved in cancer may have secondary undesirable effects," Riolo said. To prevent some of these potential side effects, the eventual goal is to develop more selective drugs, Altura said. 




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