Gene Previously Observed Only in Brain Is Important Driver of Metastatic Breast Cancer
When breast cancer becomes metastatic, patient survival is drastically reduced, prompting the need to explore the genes that may cause tumor cells to metastasize.
Now, scientists from The Wistar Institute have shown that a gene that was once thought only to be found in the brain is also expressed in breast cancer and helps promote the growth and spread of the disease. Additionally, they showed how a version of the gene with edited RNA prevents metastasis. The findings were published by Gumireddy et al in Nature Communications.
When breast cancer metastasizes, only about one in five patients survive more than 5 years. The causes of metastasis in breast cancer at a molecular level are not very well understood, so identifying regulatory genes that prompt this behavior could have a tremendous impact on survival, from early detection to the design of better treatment strategies.
“Metastatic breast cancer is ultimately what kills patients,” said Qihong Huang, MD, PhD, Associate Professor in the Tumor Microenvironment and Metastasis Program at The Wistar Institute. “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 The Cancer Genome Atlas (TCGA) and identified 41 genes inversely correlated with survival in breast cancer. Dr. Huang and colleagues focused on one gene in particular: GABAA receptor alpha3 (Gabra3). The gene was particularly intriguing, since prior to this study, researchers believed that Gabra3 was only found in brain tissue.
Implications of Gabra3
There were three main reasons the researchers determined it was worth studying: first, it's highly expressed in cancer tissues, but not in healthy breast tissues; second, it's a cell surface molecule and therefore something that could be potentially targeted by a drug; and finally, drugs that target Gabra3 are already available for treating other diseases like insomnia. The researchers showed that cells expressing Gabra3 were better at migrating and invading than their control counterparts, that Gabra3 showed metastasis-promoting activity in vivo, and animal models injected with the activated gene all developed metastatic lesions in their lungs. It does so by activating the AKT pathway, a cellular pathway essential to cell growth and survival in many types of cancer including breast cancer.
In some instances, though, certain types of Gabra3 are actually able to suppress breast cancer metastasis. This is closely linked to the RNA of the gene. Dr. Huang and colleagues found that Gabra3 that had undergone RNA editing was found only in noninvasive breast cancers. When the RNA is edited, it suppressed the activation of the AKT pathway required for metastasis, meaning that breast cancer with this specific type of Gabra3 was unable to spread to other organs. This is particularly encouraging since signaling proteins called interferons can increase RNA editing activity and could therefore prevent Gabra3 from activating the AKT pathway.
“We believe this is the first time that anyone has demonstrated the importance of RNA editing in breast cancer,” Dr. Huang said. “A combination strategy that that involves targeting Gabra3 while also upregulating the expression of RNA editing molecules could be an effective strategy for managing metastatic breast cancer.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
