2010 Molecule of the Year

Structure of the FOXM1 DNA binding. Source: Protein Data Bank.

The International Society for Molecular and Cell Biology and Biotechnology Protocols and Research (ISMCBBPR) has recognized Forkhead box protein M1 (FOXM1) as the 2010 Molecule of the Year.

The ISMCBBPR selected FOXM1 because of its growing potential as a target for cancer therapies. Last year, in a paper published in Molecular Cancer, UK researchers detailed how FOXM1 overexpression destabilizes the cell cycle, causing the cells to grow uncontrollably toward cancer development. 

In 2002, FOXM1 was first labeled an oncoprotein, a protein that could cause cancer when overexpressed. Since then, researchers have linked FOXM1 overexpression to lung, liver, breast, and brain cancers. But researchers’ limited knowledge about how the protein’s overexpression promotes cancer growth was a roadblock to the development of cancer prevention treatments.

To understand the process better, a group of researchers led by Muy-Teck Teh—a lecturer in head and neck cancer at the Barts and The London School of Medicine and Dentistry and author of the 2010 Cancer Research paper—overexpressed FOXM1 in normal adult human oral epithelial stem cells, pushing the cells toward hyperplasia, a proliferative stage that can lead to cancer.

Through this experiment, Teh and his team discovered that FOXM1 interferes with the stem cell’s growth cycle and division. Normal FOXM1 levels control cell growth. When cells divide regularly, FOXM1 coordinates the division of genetic material to the two daughter cells.

But when FOXM1 is overexpressed, Teh’s team found that the protein loses its control over cell growth, allowing cells to grow wildly. “If you overexpress FOXM1, it could possibly disturb this proper segregation of the chromosomes,” said Teh. “And that would also lead to cancer.”

FOXM1 expression is therefore becoming a popular target for the development of cancer prevention drugs. “If you get rid of FOXM1, you stop the cells from dividing,” said Teh. But elimination of the protein is not a viable option; FOXM1 is necessary for normal organ development. Previous groups observed that when the protein is removed from mice, pups die soon after birth from heart failure.

The problem becomes more complicated in humans who have three FOXM1 gene variants: FOXM1a, FOXM1b, and FOXM1c. These variants act as backups and could compensate when another variant malfunctions or is eliminated. The backups, however, may also predispose cells toward oncogenesis. “Most people study FOXM1b in cancer etiology,” said Teh. “But FOXM1c is also related to cancer but is less well known.” FOXM1a is inactive in normal human cells.

Teh and his team continue to investigate FOXM1’s function in the cell, hoping to understand how it instructs stem cells towards hyperplasia. He expects the 2010 Molecule of the Year to become an important diagnostic cancer biomarker in the near future. “We could use that information to determine whether a given biopsy contains malignant cells or not,” said Teh. 

Muy-Teck Teh. Image source: Barts and The London School of Medicine and Dentistry .