Researchers say they’ve uncovered new details that help explain how the PTEN gene exerts its anticancer effects and how PTEN loss or alteration can set cells on a cancerous course.
The team’s study, published in Cell, reveals that PTEN loss and PTEN mutations are not synonymous.
This discovery provides additional insight into basic tumor biology and offers a potential new direction in the pursuit of cancer therapies, according to the researchers.
“By characterizing the ways that 2 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,” said study author Pier Paolo Pandolfi, MD, PhD, of Beth Israel Deaconess Medical Center in Boston.
“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.”
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 showed that the PTEN mutant protein is not only functionally impaired, it also acquires the ability to affect the function of normal PTEN proteins, thereby gaining a pro-tumorigenic function. But the researchers also wanted to determine the difference between PTEN mutation and PTEN loss.
“We wanted to know, would outcomes differ in cases when PTEN was not expressed, compared with cases when PTEN was expressed but encoded a mutation within its sequence?” said study author Antonella Papa, PhD, an investigator in the Pandolfi lab.
To find out, the team created several genetically modified strains of mice to mimic the PTEN mutations found in human cancer patients.
“All mice [and humans] have 2 copies of the PTEN gene,” Dr Papa explained. “The genetically modified mice in our study had 1 copy of the PTEN gene that contained a cancer-associated mutation [either PTENC124S or PTENG129E] and 1 normal copy of PTEN. Other mice in the study had only 1 copy of the normal PTEN gene, and the second copy was removed.”
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.
“This was very surprising, as we were expecting a reduction in tumorigenesis,” Dr Papa said. “Instead, mechanistically, we found that PTEN exists as a dimer, and, in this new conformation, the mutated protein prevents the normal protein from functioning.”
At the molecular level, this generates an increased activation of a PTEN target—the protein Akt—which is what leads to the augmented tumorigenesis in the mice. Akt is part of a signaling pathway that regulates cell growth, division and metabolism.
When PTEN is prevented from inhibiting Akt, the pathway becomes overactive. As a result, targeting Akt and its pathway may be an effective treatment strategy for patients with PTEN mutations, the researchers said, adding that inhibitors to affect this pathway are currently being tested and developed.
“This defines a new working model for the function and regulation of PTEN and tells us that PTEN mutational status can be used to determine which cancer patients might benefit from earlier and more radical therapeutic interventions and, ultimately, better prognosis,” Dr Pandolfi said.
“Our findings may help to better identify and stratify patients and their response to treatment based on the different genetic alterations found in the PTEN gene. Importantly, our study shows that cancer therapy should be tailored on the basis of the very specific type of mutations that the tumor harbors.”
“This adds a new layer of complexity but also a new opportunity for precision medicine. I would say that, based on these thorough genetic analyses, this story represents the ultimate example of why personalized cancer medicine is so urgently needed.”
