Novel genes identified that help suppress prostate and other cancers

The study identified genes that cooperate with the well-known tumour suppressor gene Pten, and showed their relevance in human prostate tumours.

This research sheds light on new pathways involved in cancer development – these could be possible drug targets for cancers with a faulty Pten gene. The methods developed could also identify other genes that cooperate to suppress cancer growth.

Tumour suppressor genes such as Pten help prevent cancer development in healthy people. Pten regulates an important cell pathway for growth and division. However, little is known about which other genes and pathways cooperate with Pten to prevent cancer.

In this study, researchers designed a new method in mice in which part of the Pten gene was converted into a mobile DNA element known as a transposon.  When this was mobilised from the Pten gene it was inactivated.  Importantly the transposon carrying a piece of Pten would land randomly throughout the genome, damaging genes into which it inserted.  Cancers would grow when the transposon damaged a tumour suppressor gene that co-operated with Pten.

Dr Jorge de la Rosa, the first author on the study from the Wellcome Trust Sanger Institute, said:  “We developed a new method that coupled Pten inactivation with mobilisation of the transposon.  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.

Tumour analysis

The researchers analysed 278 prostate, breast and skin tumours from the mice and revealed hundreds of genes that could cooperate with Pten and act as further tumour suppressor genes. Human cell lines and data from human prostate tumours were then used to study the five most promising genes.

Dr Juan Cadiñanos, joint lead author from the Instituto de Medicina Oncologica y Molecular de Asturias, in Spain, said: “This is the first study to look specifically for tumour suppressor genes that cooperate with Pten in a range of cancer types. We found that genetically inactivating Pten and each of the five 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 five genes than usual, indicating that these pathways may be important for suppressing tumours.”

Wac gene

The researchers also studied one of the five genes, called Wac, in transgenic mice with mutant Pten. They discovered that removing one copy of Wac increased the size of prostate tumours, as expected for a tumour suppressor. However, removing both copies in the genome surprisingly reduced the size of the tumours. This could reveal new pathways to target for treating prostate cancer.