As with many proteins in cancerous cells, Akt actually exists as a "family" of related proteins, consisting of Akt1, Akt2 and Akt3, explains Chin, an Instructor of Pathology at BIDMC and HMS. "In breast cancer, Akt1 and Ak2 are found, and are frequently hyperactivated due to genetic mutations in the pathway. But we now know that the two family members have opposing functions such that Akt1 inhibits, while Akt2 enhances invasion into the local tumor stroma, leading to metastasis."
To identify novel downstream targets of Akt proteins in breast cancer, the scientists used a discovery-based proteomics approach, coupled with analyses of breast cancer cell lines derived from patients with aggressive metastatic disease. This widely used approach led the authors to identify palladin, a protein known to regulate cell motility and named after the Italian Renaissance architect Andrea Palladio and the Palladian style of architecture.
"Palladin's normal function is to inhibit cell migration and keep cells in place," explains Toker. "By organizing the cellular cytoskeleton at the molecular level, palladin maintains the architecture of the cell in a highly organized manner." But, he adds, because Akt1 regulates palladin in an exclusive manner (by blocking cell motility) when palladin is lost, cells become disorganized, leading to a marked increase in cell migration. "It is believed that the end result is enhanced metastasis, a hypothesis that our lab is continuing to investigate using mouse models of disease progression," notes Toker.
Since the mid-1990s, scientists have known that there exist more than 100 targets of Akt proteins. "But among all of these, only a handful have been shown to be specific to either Akt1 or Akt2," adds Toker. "Our discovery really is the first example of this type of specific mechanism in the Akt pathway, and understanding specific targets is of enormous importance for pharmacological purposes."
|Contact: Bonnie Prescott|
Beth Israel Deaconess Medical Center