STAT3’s role depends on the presence of EGFR or PTEN, according to study in Genes and Development.

Scientists at Harvard Medical School report that a previously implicated glioblastoma oncogene becomes a tumor suppressor gene in some types of this cancer. STAT3 has been shown to become a driving force in brain tumor development.

Since nearly all brain cancers occur in astrocytes or in the neural stem cells that generate astrocytes, the research team decided to study whether certain regulatory genes that control the generation of astrocytes during normal development also play a role in these tumors. STAT3 is known to turn neural stem cells into astrocytes during normal development.

The study began by genetically manipulating mouse astrocytes, then placing them into a second group of mice whose immune systems had been compromised.

Taking advantage of previously published data, the investigators looked closely at how two genes, EGFR and PTEN whose mutated forms are associated with glioblastoma, affect the function of STAT3 in astrocytes. They found that when EGFR is mutated, STAT3 is an oncogene. With a PTEN mutation, however, STAT3 is a tumor suppressor.

“EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface,” explains Azad Bonni, M.D., Ph.D., an associate professor of pathology at Harvard Medical School, and senior author on this study. “However, when it’s mutated, we find it in the cell’s nucleus interacting with STAT3 and turning it into an oncogene. STAT3 itself is not mutated or damaged. It’s the process of regulating STAT3 that gets damaged.”

PTEN, on the other hand, is itself a tumor suppressor gene. When PTEN becomes disabled in astrocytes, these potential tumors still have STAT3 standing in their way. This is because STAT3 normally acts as a tumor suppressor in astrocytes. As more PTEN becomes disabled, though, STAT3 function gets inhibited, allowing tumor formation.

The researchers say that they confirmed these findings in human glioblastoma tumors as well.

While glioblastoma tends to be uncommon, STAT3 has also been implicated in prostate and breast cancers, according to the team. They believe that these results may also translate to other types of tumors.

Besides researchers at Harvard Medical School, collaborators included investigators at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, the Belfer Institute for Innovative Cancer Science, and New York University School of Medicine. The results appeared online in the February 6 issue of Genes and Development.

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