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Expression of Gabra3 Activates AKT Pathway to Promote Breast Cancer Metastasis, Study Finds

NEW YORK (GenomeWeb) – Expression of the GABA receptor Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion, and metastasis, according to researchers from the Wistar Institute and elsewhere.

As they reported in Nature Communications today, Wistar's Qihong Huang and his colleagues sifted through The Cancer Genome Atlas data to uncover 41 genes whose expression was inversely correlated with breast cancer survival. They then homed in on one of those, GABAA receptor alpha3 (Gabra3), and found that although its expression has mostly been previously described in the brain, it is involved in breast cancer metastasis.

In addition, the researchers reported that non-invasive breast cancers harbor an ADAR-edited version of Gabra3 that actually suppresses invasion and metastasis rather than promoting them.

While breast cancer is largely treatable when caught early enough, metastatic breast cancer has a five-year survival rate of about one in five. "Metastatic breast cancer is ultimately what kills patients," Huang said in a statement. "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."

Huang and his colleagues searched through TCGA RNA-seq data from both breast cancer and normal tissue along with survival data to uncover genes needed for breast cancer progression. From this, they found 41 genes whose up- or down-regulation was linked to poor survival.

They focused their further analyses on Gabra3, as it is expressed in breast cancer tissues but not normal breast tissues, and as it is a cell surface molecule against which there are already drugs, though for other conditions.

Gabra3 is strongly expressed in adult brain tissue, as compared to other normal adult tissues, though it is even more strongly expressed in fetal brain tissue, the researchers noted. Meanwhile, they added, it is expressed at various levels in breast cancer cell lines, but not in normal human epithelial cell lines. Further, its expression is higher in metastatic breast cancer than in matched primary breast cancer samples, suggesting that its expression is linked with poorer survival.

In a series of breast cancer cell line-based analyses, Huang and his colleagues found that breast cancer cells expressing increased Gabra3 levels showed higher-than-usual levels of migration and invasion. In addition, mice injected with cells expressing Gabra3 all developed metastases while none of the mice given a control vector did.

At the same time, knockdown of Gabra3 with short hairpin RNA constructs reduced the migration and invasion abilities of cancer cell lines, and fewer mice given the Gabra shRNA developed metastases as compared to those given a control shRNA. This, the researchers said, indicates that Gabra3 is "both sufficient and required for breast cancer metastasis."

In the brain, Gabra3 undergoes A-to-I RNA editing via ADAR, the researchers noted. But, in breast cancer tissues, Huang and his colleagues only uncovered RNA editing of Gabra3 in non-invasive breast cancer cell lines. Additionally, in a set of matched primary and metastatic tumor samples, only the primary samples expressed edited Gabra3.

Increased ADAR1 expression, they further found, decreases migration and invasion. Mice transplanted with cells expressing RNA edited Gabra3 had reduced lung metastases as compared to mice given cells expressing a control vector.

This, Huang and his colleagues added, suggests that edited Gabra3 has an opposing function to unedited Gabra3.

While the downstream signaling pathways mediated by Gabra3 are unknown, Huang and his colleagues examined how it affects AKT activation, as the AKT pathway has been shown to be a critical part of breast cancer metastasis.

In a breast cancer cell line, ectopic expression of RNA-edited Gabra3 reduced the level of phosphorylated AKT, though had no effect on the total AKT level, they reported. Meanwhile, overexpression of unedited Gabra3 increased the levels of phosphorylated AKT in another breast cancer cell line, an increase that the researchers noted could be reversed by overexpressing A-to-I edited Gabra3.

These and other results suggested to the researchers that unedited Gabra3 activates AKT pathways, though RNA-edited Gabra3 suppresses AKT activation.

"We believe this is the first time that anyone has demonstrated the importance of RNA editing in breast cancer," 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."