Circadian rhythm gene affects malignant breast cancer's spread

Sleep cycle interruptions may affect breast cancer formation and metastasis.

Expression of a gene in the circadian rhythm pathway, Arntl2, has a significant effect on whether certain breast cancers will metastasize into additional tumors, reports Kent Hunter of the National Cancer Institute (NCI) in Bethesda, Maryland and colleagues in a study published in PLOS Genetics.

Patients with a highly malignant form of breast cancer called estrogen receptor-negative (ER-) breast cancer generally have poor prognoses, primarily because doctors have no targeted therapies aimed at the metastases, which are more deadly than the initial tumor. Relatively little is understood about how metastatic breast cancer forms secondary tumors, so NCI scientists singled out genes associated with breast cancer's spread by interbreeding a mouse model with a high rate of breast cancer metastasis to a model with a low rate. They identified the circadian rhythm gene Arntl2 as being linked to metastasis in ER- breast cancers. Using CRISPR/Cas9 gene editing to alter expression levels of the gene, they showed that Arntl2 expression affects the burden of metastatic tumors. Furthermore, an analysis of inherited genetic variations in human breast cancer patients and their survival rates confirms the role of Arntl2 expression in breast cancer progression.

These studies not only provide additional information on the mechanisms of how ER- breast cancers metastasize, but also suggest that the interruption of normal sleep cycles may play a role in the progression of localized breast cancer to life-threatening metastatic tumors. While the five-year survival rate for women with localized breast cancer is almost 99 percent, women with distant metastases have a survival rate of just 26 percent, emphasizing the need for new approaches to treat metastatic tumors.

This study was funded partially by the DOD IDEA grant BC122861 and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

Article: The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer, Ha N-H, Long J, Cai Q, Shu XO, Hunter KW, PLOS Genetics, doi:10.1371/journal.pgen.1006267, published 22 September 2016.