Body clock gene may help lethal spread of breast cancer



Can the body’s circadian rhythms influence cancer? Shift workers are more prone to cancer, and now a study in mice has found that changes to a gene that regulates the circadian clock seem to increase the likelihood of breast cancer spreading and becoming deadly. The finding could mean that disrupted sleep may worsen a person’s breast cancer prognosis.

Breast cancer is the most common type of cancer in women. Provided it’s diagnosed early, survival rates can be as high as 99 per cent, but this plummets to only 26 per cent if the cancer has spread elsewhere. “In most solid tumours, particularly breast cancer, patients succumb not to the primary tumour, but to metastatic disease,” says Kent Hunter at the National Cancer Institute in Bethesda, Maryland.

Oestrogen receptor negative (ER-) breast cancer is a particularly difficult type to treat once it has spread, so a better understanding of how it does this is urgently needed. Previous studies hinted that genetics might influence an individual’s risk of a cancer spreading, so to try to identify specific genes involved, Hunter and his team interbred mice predisposed to develop a particularly aggressive form of metastatic breast cancer with those at low risk of metastasis.

Doing this pinpointed a circadian rhythm gene, Arntl2, which codes for a protein that binds to and controls the activity of other genes within a cell. The team then used gene-editing to alter its activity in cancer cells, and injected these into cancer-free mice. A month later, those injected with high Arntl2-activity cells had far more metastatic growths than those that received cells with low Arntl2 activity.

Turning to humans with ER- cancer, the team found that those who had inherited more active variants of Arntl2 were less likely to have survived their cancer.

Long-term shift work is known to be associated with a higher risk of developing breast cancer, but little is known about how circadian rhythms might influence the spread of tumours.

“The fact that inherited variations in this gene seem to be associated with progression of cancer raises the possibility that disruptions to normal circadian rhythms might have an effect [on metastasis],” says Hunter.

Loss of a gene related to Arnt12 does seem to be associated with an increase in lung cancer, an effect that is enhanced when lung cancer mice are put on a sleep schedule resembling jet lag, says Chi Van Dang, director of the Abramson Cancer Centre in Pennsylvania.

But Hunter’s team did not study circadian behaviour in their mice, so it is unclear whether altering Arntl2affects the body clock and if this contributes to increased metastasis, says Dang.

However, there is some evidence that it might. A recent study suggested that Arntl2 can raise the activity of a set of genes associated with metastasis and a poor prognosis in lung adenocarcinoma, says Simon Archer at the University of Surrey in Guildford, UK.

Journal reference: PLoS Genetics, DOI: 10.1371/journal.pgen.1006267


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