Genetic Analysis May Prevent Development of Multiple Cancers

Investigators identified genes that work together with the tumor suppressor gene PTEN to prevent the development of breast, prostate, and skin cancer in mice.

In the UK, approximately 47,000 men are diagnosed with prostate cancer per year. It is the second most common cancer in men, and more than half of prostate cancers have an altered or missing PTEN gene.

PTEN is a tumor suppressor that works to prevent the development of cancer in healthy individuals.

Tumor suppressor genes work to prevent the development of cancer in healthy individuals. Scientists know that PTEN regulates an important cell pathway for growth and division, but little is known about other genes and pathways that cooperate with PTEN to prevent cancer.

In a study published in Nature Genetics, investigators designed a novel method in mice that involved converting the Pten gene into a transposon. When it was mobilized from the Pten gene it became inactive.

Most importantly, the transposon carrying a piece of the Pten gene would randomly land throughout the genome, damaging the genes it inserted into. When the transposon damaged a tumor suppressor gene that cooperated with Pten the cancers begin to grow.

“We developed a new method that coupled Pten inactivation with mobilization of the transposon,” said first author Dr Jorge de la Rosa. “We inserted the transposon directly inside the Pten gene, so that whenever it jumped out and inserted into another part of the genome, it inactivated Pten at the same time. By analyzing which genes were disrupted in the cancers that grew, we were able to pinpoint genes that cooperate with Pten in suppressing tumors.”

For the study, investigators analyzed 278 breast, prostate, and skin tumors from mice to identify hundreds of genes that could cooperate with Pten and act as further tumor suppressor genes. Next, human cell lines and data from human prostate tumors were used to study the 5 most promising genes.

“This is the first study to look specifically for tumor suppressor genes that cooperate with Pten in a range of cancer types,” said joint lead author Dr Juan Cadiñanos. “We found that genetically inactivating PTEN and each of the 5 candidate genes in human cell lines did drive cancerous changes in the cells. We also discovered that human prostate cancer samples had lower levels of expression from the 5 genes than usual, indicating that these pathways may be important for suppressing tumors.”

The investigators further examined 1 of the 5 genes called Wac in transgenic mice with mutant Pten. The results of the study showed that removing 1 copy of Wac increased the size of prostate tumors, as expected. But when both copies were removed in the genome, the investigators were surprised to find it reduced the size of the tumors. The findings suggest a potential new pathway target for treating prostate cancer.

“Drugs that target PTEN related pathways are under development, but tumors quickly develop resistance,” said joint lead author Allan Bradley. “It would therefore be useful to also target other tumor suppressor pathways. This new method is a good way of highlighting important tumor suppressor networks, and we hope the genes identified in this study will provide a basis for the development of therapeutic strategies for prostate and other cancers.”