A new Canadian study has discovered a gene that stops cancer tumours in a range of cancers, including breast, lung and liver. The researchers hope the discovery will help to improve treatments for many cancer patients.

The study is published in the early online issue of Nature Medicine.

Dr. Poul Sorensen a senior scientist at the British Columbia Cancer Research Centre and Professor at the Department of Pathology & Laboratory Medicine, University of British Columbia, led the research team of scientists from Canada, the US and Austria.

The growth of cancerous tumours is influenced at the genetic level by the balance between genes that help cancerous cells to multiply and form tumours (oncogenes) and genes that stop them forming tumours (tumour suppressor genes). The balance can be tipped in favour of tumour growth by low expression or inactivation of tumour suppressors.

Sorensen and colleagues had already discovered in previous studies that the tumour suppressor gene HACE1 is frequently inactivated ("downregulated") in human tumours in cancers such as lymphoma, breast and lung cancer. They had a hunch that low expression of the gene allowed cancerous cells to form tumours, so they decided to investigate what happens when HACE1 is switched on and off.

Using laboratory mice the researchers showed that switching off the HACE1 gene triggered late-onset cancer and tumour growth of a range of cancers, including breast, lung and liver cancer. They used a "gene silencing" technology known as Small interfering RNA (siRNA) to turn the gene off.

When Sorensen and his team injected the mice to turn the HACE1 gene back on, the tumours stopped growing.

The scientists also found that tumour growth triggered either by environmental factors (for instance being exposed to ultraviolet radiation and carcinogens) or by inheriting only one strongly suppressive version of another tumour suppressor gene, p53 (as opposed to inheriting strong variants or alleles from both parents) was faster in mice with low background levels of HACE1 expression.

HACE1 is in the class of genes known as E3 ubiquitin ligase, located on a region of chromosome 6q21 that is often involved in a range of human cancers.

The researchers said that HACE1 is probably helping to stop the tumours from growing by two mechanisms that arise in E3 ligase activity. One is by preventing adhesion-dependent growth, and the other is by stopping the activity of an oncogene, Cyclin D1. Cyclin D1 has been found to be over-expressed in more than 50 per cent of breast cancers for example. It plays an important role in controlling cell cycles.

The researchers concluded that HACE1 is an important chromosome 6q21 tumor-suppressor gene involved in multiple cancers and they hope its discovery will help improve treatments for a wide range of cancers.

For instance it may one day be possible either to activate HACE1 in people where it is switched off, or to stop cancer cells from switching it off.

"The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers."
Liyong Zhang, Michael S Anglesio, Maureen O'Sullivan, Fan Zhang, Ge Yang, Renu Sarao, Mai P Nghiem, Shane Cronin, Hiromitsu Hara, Nataliya Melnyk, Liheng Li, Teiji Wada, Peter P Liu, Jason Farrar, Robert J Arceci, Poul H Sorensen & Josef M Penninger.
Nature Medicine Published online: 12 August 2007.

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Written by: Catharine Paddock