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Subtle changes in PTEN tumor suppressor gene can determine cancer susceptibility
Date:4/23/2010

he absence of a full blown genetic mutation."

Tumor suppressor genes function to slow down cell division, repair DNA and help alert damaged cells when it is time to die, and PTEN is one such example. (In addition to preventing uncontrolled cell growth, PTEN is also responsible for controlling cell movement or migration, controlling the adhesion of cells to surrounding tissues and helping to control the formation of new blood cells.) But, when TSGs are absent or malfunctioning as is the case of a genetic mutation cells can multiply too quickly, growing out of control and leading to the development of cancerous tumors.

In recent years, with the advent of functional genomics, the idea that subtle changes in TSG levels could influence tumor development had been proposed but not formally investigated. To test this hypothesis, the Pandolfi team created a mouse model of PTEN that expressed the gene at approximately 80 percent of total levels. Next, they used a gene targeting approach which drives a transcriptional interference of the PTEN gene, resulting in inefficient protein production. The authors report that the presence of one targeted allele resulted in approximately 80 percent of PTEN expression relative to the normal level of PTEN expressed in specific tissues in this case, mammary gland tissue. And, as predicted, the scientists subsequently identified an increased incidence of mammary tumors in these mice, and through a careful histopathological and molecular analysis were able to demonstrate that mammary tumors maintained both the targeted and wild-type PTEN alleles intact.

"These mice showed mammary cancer at a high incidence and in the absence of further alterations to the PTEN gene," explains Pandolfi. "This confirms that the PTEN gene is a 'quasi-insufficient' tumor suppressor, such that even a subtle 20 percent decrease in gene expression is sufficient to impair its full tumor-suppressive activity."

This discovery, sa
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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