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August 8, 2006

Hunt for DNA Amplified in Cancers Uncovers Important Target Gene

Topics: Medical Science News

Gene amplification links growth controlling pathway from the tiny fruit fly to human cancers.

Researchers at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH) have discovered a new cancer-promoting role for a gene potentially involved in breast, liver, and other kinds of cancers. Their discovery that the YAP (Yes-associated protein) gene can transform mammary epithelial cells opens the door to understanding how a novel cell growth controlling pathway first discovered in fruit flies might be important in human cancers.

"We screened the DNA from breast cancer cells for amplifications that are associated with tumor development. The identification of these new potential cancer-causing genes is critical to uncovering novel pathways that drive the conversion of a normal cell to a cancerous one." says senior author Daniel Haber, MD, PhD, the Laurel Schwartz professor of medicine at HMS and MGH and director of the MGH Cancer Center. This research was conducted jointly by Haber's lab and the lab of Joan Brugge, PhD, professor and chair of the Department of Cell Biology at HMS.

Through microarray analysis of a mammary tumor in a BRCA1/p53 deficient mouse model, Haber's group discovered an amplified region of DNA in the mouse breast tumor that contained only one known gene, called YAP.

"A similar region of DNA is also amplified in some human tumors, but this amplified region often contains other genes that are known to promote cell survival," says Haber, who worked with co-authors Jianmin Zhang, PhD, and Gromoslaw Smolen, PhD, both research fellows at MGH. "Thus, whether the YAP gene could play a role in these cancers had been largely ignored. The amplified region we discovered excluded these other genes, which allowed us to focus on YAP as a new candidate."

The YAP gene has an interesting literature associated with it that comes from the fruit fly Drosophila melanogaster. The Drosophila version of the YAP gene, called Yorkie (Yki), functions to promote both cell division and cell survival and is controlled by several other genes called Hippo (Hpo), Salvador (Sav), Warts (Wts), and Mats. The mutation of any of these upstream genes or the overexpression of Yki causes dramatic overgrowth of cells in the Drosophila eye or wing. This coupling of cell division and cell survival is unique - other genes that promote cell division, for example, Myc, also sensitize a cell to death.

"To use the car analogy that is often applied to cancer models, activation of Myc is like stepping on the gas to activate cell division but also lightly tapping on the brakes at the same time, so that should anything go wrong during division, the car can very quickly be stopped, or the cell can be removed by cell death," says first author Michael Overholtzer, PhD, research fellow in cell biology at HMS. "Yki activation, on the other hand, is like stepping on the gas and disabling the brakes at the same time. Such an activity would be thought to be coveted by cancer cells. Therefore these genes, Yki (YAP), Hpo, Sav, Wts, and Mats, most of which were first discovered in the fruit fly, represent a relatively new and exciting pathway that might control human cancers."

Continue reading at EurekAlert...

Posted by Richard at August 8, 2006 10:40 PM


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