Wistar Institute researchers studying the genes and molecules involved in breast cancer progression have found that a gene previously thought to be present only in brain tissue promotes metastasis in vivo, and correlates with poor breast cancer survival. Importantly, researchers also found that an edited version of this gene suppresses breast cancer cell invasion and metastasis, highlighting the importance of RNA editing in this malignancy.
The research paper, “The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis,” was published in Nature Communications.
Cancer stage at diagnosis determines determinant not only the treatments given to patients but also their chances of survival. According to the National Cancer Institute, the five-year survival for localized female breast cancer, or stage 1, is 98.6 percent. However, when the cancer has metastasized, referred to either as regional or distant, five-year survival can be as low as 25.9 percent.
To investigate the genes involved in metastatic events in breast cancer, researchers analysed The Cancer Genome Atlas (TCGA) breast cancer data and found 41 genes that were inversely correlated with cancer survival. The study mainly focused on the gene GABAA receptor alpha3 (Gabra3), a gene previously thought to be exclusive to adult brain tissues. The team found that this gene is highly expressed in breast cancer tissues, but not in healthy breast tissue. Furthermore, researchers showed that cells expressing Gabra3 had superior migrating and invading skills when compared to cells that did not express it. The gene showed metastasis-promoting activity in vivo, due to its ability to activate the AKT pathway, a cellular pathway essential to cancer cell survival and growth.
Gabra3 that underwent RNA editing, however, was found only in non-invasive breast cancers. Upon RNA editing, the gene suppressed the activation of the AKT pathway — necessary for metastasis — and breast cancer with this specific type of Gabra3 was not able to spread to other organs. Qihong Huang, MD, the study’s lead author and an associate professor in the Tumor Microenvironment and Metastasis Program at The Wistar Institute, said in a press release, “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.”
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