New insights gained into how the PTEN tumor suppressor gene exerts its anticancer effects
PTEN loss and PTEN mutations are not synonymous, according to a new study. It provides key insights into basic tumor biology and also offers a potential new direction in the pursuit of new cancer therapies.
Ever since it was first identified more than 15 years ago, the PTEN gene has been known to play an integral role in preventing the onset and progression of numerous cancers. Consequently, when PTEN is either lost or mutated, malignant cells can grow unchecked, and cancer can develop.
Now a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts, has helped to explain more precisely how PTEN exerts its anticancer effects and how its loss or alteration can set cells on a cancerous course. The new study was reported in Cell (2014; doi:10.1016/j.cell.2014.03.027).
"By characterizing the ways that two specific PTEN mutations regulate the tumor suppressor function of the normal PTEN protein, our findings suggest that different PTEN mutations contribute to tumorigenesis by regulating different aspects of PTEN biology," explained senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center at BIDMC.
"It has been suggested that cancer patients harboring mutations in PTEN had poorer outcomes than cancer patients with PTEN loss. Now, using mouse modeling, we are able to demonstrate that this is indeed the case. Because PTEN mutations are extremely frequent in various types of tumors, this discovery could help pave the way for a new level of personalized cancer treatment."
The PTEN gene encodes a protein that acts as a phosphatase, a type of enzyme that removes phosphates from other substrates. Several of the proteins that PTEN acts upon, both lipids and proteins, are known to promote cancer when bound to a phosphate. Consequently, when PTEN removes their phosphates, it is acting as a tumor suppressor to prevent cancer. When PTEN is mutated, it loses this suppressive ability, and the cancer-promoting proteins are left intact and uninhibited.
This new study unexpectedly showed that the PTEN mutant protein is not only functionally impaired (losing its enzymatic function) it additionally acquires the ability to affect the function of the normal PTEN proteins, thereby gaining a pro-tumorigenic function.
The scientific team created several genetically modified strains of mice to mimic the PTEN mutations found in human cancer patients. The researchers found that the mice with a single mutated copy of PTEN were more tumor-prone than the mice with a deleted copy of PTEN. They also discovered that the mutated protein that was produced by PTENC124S or PTENG129E was binding to and inhibiting the PTEN protein made from the normal copy of the PTEN gene.
The mutated protein generates increased activation of Akt, a PTEN target. This suggests that targeting Akt may be an effective treatment strategy for patients with PTEN mutations. Inhibitors that affect this pathway are currently being tested and developed.