A gene previously thought only to be expressed in the brain, GABAA receptor alpha3 (Gabra3), promotes breast cancer migration, invasion, and metastasis, according to a recent study.1
When detected early, breast cancer is highly treatable and survivable. However, overall survival plummets when breast cancer metastasizes: only approximately 1 in 5 patients with metastatic breast cancer will remain alive at 5 years.
“Metastatic breast cancer is ultimately what kills patients,” said lead author Qihong Huang, MD, PhD, associate professor in the Tumor Microenvironment and Metastasis Program at The Wistar Institute, Philadelphia, Pennsylvania.
“While early detection is critical, it does not help patients whose disease has spread, and so we wanted to determine what was causing this to happen.”
The researchers analyzed breast cancer from The Cancer Genome Atlas, which is operated by the National Cancer Institute and the National Human Genome Research Institute. They discovered 41 genes whose expression in decreased in people who survive metastatic breast cancer.
This study further examined Gabra3, showing that increased expression of Gabra3 correlated with low metastatic breast cancer survival. The researchers used cell cultures and mice to show that Gabra3 activates the AKT pathway, which is a pathway involved in cancer migration, invasion, and metastasis.
The discovery of an RNA-edited version of Gabra3 only in patients with noninvasive breast cancers suggested a mechanism for resistance to metastases. These RNA-edited versions of Gabra3 suppressed the AKT pathway.
“We believe this is the first time that anyone has demonstrated the importance of RNA editing in breast cancer. A combination strategy that involves targeting Gabra3 while also upregulating the expression of RNA editing molecules could be an effective strategy for managing metastatic breast cancer,” explained Huang.
Researchers at the Wistar Institute are hoping to develop existing GABAA receptor antagonists for Gabra3 overexpressing tumors and for oncology therapeutics and treatment.
1. Gumireddy K, Li A, Kossenkov AV, et al. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. [Published online ahead of print February 12, 2016]. Nat Commun. doi:10.1038/ncomms10715.