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Screening approach leads to discovery of gene linked to breast cancer

es to identify an important breast cancer gene," he continues. "Each method helps 'filter' the information from the previous one, enabling us to zero in on the strongest candidate."

Hahn and his colleagues focused on a class of proteins known as kinases, which serve as molecular starting guns for chemical reactions within cells. Overproduction of certain kinases has been linked to a variety of cancers. To determine which, if any, kinases play a role in breast cancer, investigators conducted a sequence of experiments to refine their results.

They began with a cell protein called Ras, a courier of signals from the cell surface to the interior. Abnormalities in Ras or its partner proteins -- including kinases -- occur in the vast majority of "epithelial" cancers, which, like breast cancer, arise in the lining of bodily tissues. Ras transmits signals to a variety of "downstream" proteins -- among them, proteins called MEK or PI3K. When both of these become active at the same time, cells become cancerous, investigators found.

The team then created a set of 354 human kinases and injected each into normal epithelial cells to see if any mimicked PI3K's ability to transform them into cancer cells. They found five that did.

To narrow this field, investigators conducted a second group of screening procedures. Using a variety of genome-scale approaches, they sought to determine if genes for any of the five kinases were unusually abundant in cancer cells. They found extra copies of IKBKE, but not of the other genes -- and correspondingly high levels of the IKBKE protein. This pointed to IKBKE's role as a breast cancer oncogene.

In the third part of the study, the investigators explored whether breast cancer cells depend on IKBKE for survival. In an earlier study, they had used a technique called RNA interference -- whose discovery was recognized with the Nobel Prize in Medicine and Physiology last year -- which uses bits of gen
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Contact: Teresa Herbert
teresa_herbert@dfci.harvard.edu
617-632-4090
Dana-Farber Cancer Institute
14-Jun-2007


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