Scientists at Dana-Farber Cancer Institute found that a mutation in the gene IKBKE leads to protein overexpression and that this protein causes cell growth and proliferation.
Unlike breast cancer-susceptibility genes such as BRCA1 and BRCA2, IKBKE is not inherited in a mutated form. Rather, the mutation arises during a woman's life. The researchers believe this mutation is found in 30–40% of all breast cancers.
The team initially focused their attention on kinases. They began with a cell protein called Ras, a courier of signals from the cell surface to the interior. Ras transmits signals to a variety of downstream proteins, among them MEK or PI3K. When both of these become active at the same time, cells become cancerous, discovered the investigators.
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.
Then, 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 in cancer cells.
Finally, the investigators explored whether breast cancer cells depend on IKBKE for survival. Using high-throughput RNAi, they found that when IKBKE was switched off, the cancer cells tended to stop proliferating and died.
The study was done in collaboration with researchers at Brigham and Women's Hospital and the Broad Institute of Harvard and MIT. It will be reported in the June 15 issue of Cell.