New gene presents a potent new target for breast cancer therapy

A gene known to promote longevity in animals has now been discovered to encode a tumor suppressor – a protein that helps prevent cancer, according to a study by a team of scientists from The University of Texas M. D. Anderson Cancer Center. The new gene, which was inactivated in two-thirds of patients studied, presents a potent new target for breast cancer therapy, the researchers say.

In a study published in the April 16, 2004, issue of the journal Cell, scientists describe how the presence of the protein, named Forkhead box class O3 (FOXO3), is associated with better outcomes for breast cancer patients. Conversely, if FOXO3 was inactivated, patients had worse outcomes.

“This is a very good prognostic marker for breast cancer patient outcome,” said Mien-Chie Hung, Ph.D., the co-principal investigator of the study. “In addition, these proteins provide new targets for cancer therapy and prevention.”

The research team, which was a collaboration between the laboratories of Mickey C.-T. Hu, Ph.D., and Hung, both of the Department of Molecular and Cellular Oncology at M. D. Anderson, demonstrated that FOXO3 is inactivated in many cancer patients by an enzyme called IKK and determined that IKK is an oncoprotein, a protein that can induce cancer.

“We have uncovered two important events and put them together in one story,” says Hung. “This research has identified an important new tumor suppressor protein and a new oncogene that provide targets for cancer therapy. Previously, these proteins had been suspected to be involved in cancer, but there was no direct evidence for that.”

The IKK oncoprotein belongs to a family of enzymes called kinases. Researchers have shown that blocking certain kinases can be an effective way to block cancer. New generation cancer drugs such as Gleevec, which has been effective in treating leukemia patients, work by zeroing in and inactivating a kinase molecule. Such targeted therapies are designed to kill cancer cells while avoiding serious damage to other, non-cancerous cells.

The scientists discovered the protein’s role in cancer while studying how normal cells can turn cancerous. They showed that IKK can attach to the FOXO3 protein and inactivate it. When the normal function of FOXO3 is blocked, the cell can multiply unchecked.

Once they had established that inactivated FOXO3 protein could lead to cancer, the researchers examined its role in tumor cells from 131 breast cancer patients. They found FOXO3 in 113 out of 131 samples. Of the 113 samples with FOXO3, the protein was inactive in 83 and active in 30 samples. When they looked at patient survival, they found a strong correlation between active FOXO3 and better patient survival. Additional research revealed the FOXO3 protein can be found in patients with stomach, liver and lung cancer. However, the scientists did not study enough of these patient samples to say how important the gene is in these cancers.

In additional laboratory studies, the scientists demonstrated that a slightly altered form of FOXO3 that can’t be inactivated by IKK acts as an even more potent tumor suppressor than the normal FOXO protein.

“This mutant FOXO3 may be an even more powerful tumor suppressor than the normal FOXO3 protein,” says Hung. “This finding may provide a new avenue for cancer gene therapy or other targeted cancer therapies.”

The presence of active Forkhead (FOXO) protein has been linked to longevity in laboratory animals such as the nematode worm, says Hung. Hu and Hung’s discovery that FOXO3 is a tumor suppressor may provide a clue to the gene’s ability to increase lifespan in animals. But exactly how a tumor suppressor could increase lifespan remains a mystery.

“That is the million-dollar question,” Hung says.

The research was supported by grants from the National Institutes of Health, the M. D. Anderson Breast Cancer Research Program, the Susan G. Komen Breast Cancer Foundation, and a Cancer Center Supporting Grant. All authors of the study, who included Dung-Fang Lee, Weiya Xia, M.D., Jer-Yen Yang, Yiyu Zou, Ph.D., Shilai Bao, Ph.D., and Ryuji Kobayashi, Ph.D., are of the M. D. Anderson Cancer Center.