Gene amplification links growth controlling pathway from Drosophila 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 gene YAP 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. This work is published in the Aug. 8 online early edition of the Proceedings of the National Academy of Sciences and will appear in the Aug. 15 print edition.

"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."

Earlier studies on YAP function in human cells did not support the notion that YAP might be a cancer causing gene because its overexpression actually promoted cell death rather than cell survival (like Yki in Drosophila). Nevertheless, due to the amplification of YAP in a mouse breast tumor, Overholtzer and colleagues decided to examine the functions of YAP in a 3D mammary culture model developed in Brugge's lab.

In this model, they grew cells in a 3-dimensional protein matrix rather than in 2-dimensions on plastic, which allows mammary cells to adopt an architecture in culture that is similar to what occurs in the human breast. They had previously uncovered the effects of other genes using this model that would be missed in more conventional 2D models.

Using these 3D cultures, the authors were able to show that the overexpression of YAP caused a dramatic change in cell behavior associated with invasion into the protein matrix. This type of invasive activity is normally associated with strong acting cancer-promoting genes. The authors were further able to show, in 3D cultures and other assays, that YAP overexpression both activated cell growth and inhibited cell death, just as one might have predicted from the studies of Yki in Drosophila.

Moreover, YAP overexpression was able to turn their non-cancerous mammary cells into cancer-like cells in the lab, as evidenced by the ability of YAP expressing cells to grow in soft agar, an assay that measures cancerous potential. Parallel to Overholtzer and colleague's work, the lab of Scott Lowe, PhD, of Cold Spring Harbor, also showed that YAP overexpression could contribute to the development of liver tumors in a mouse model (Cancer Cell, July 2006). Thus, it appears that YAP is indeed a newly identified cancer-causing gene.

"What we would like to understand next is how YAP is controlled by the Hpo-Sav-Wts pathway in human cells", says Overholtzer. "Also, although we found the YAP amplification in a mouse breast tumor, in human cancers this amplicon is actually much more common in other types such as lung, pancreatic, ovarian, and others. Thus it is possible that YAP plays an important role in the development of many different types of cancer."

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