MicroRNA suppresses NF-κβ pathway, metastatic breast cancer
Ectopic expression of endogenous microRNA-146 suppresses Nuclear Factor (NF)-κβ and reduces the metastatic potential of breast cancer cells cultured in vitro, US scientists report.
The team from the Lawrence Berkeley National Laboratory in California claims that modulating microRNA-146 levels in this way has therapeutic potential in treating women with advanced breast cancer that has spread to distant sites.
Constitutive activation of the NF-κβ pathway has been implicated in advanced breast cancer and is hypothesized to promote proliferation, survival, angiogenesis, and metastasis.
However, the mechanisms underlying constitutive NF-κβ activity in cancer cells remains poorly understood, G Scott and colleagues note in the journal Oncogene.
Anecdotal evidence suggests that microRNA-146a and microRNA-146b suppress NF-κβ through a negative feedback loop.
In support of this finding, a recent study showed that loss of microRNA-146a expression results in progression of hormone-refractory prostate cancer.
Scott and colleagues investigated this theory further in the highly metastatic breast cancer cell line MDA-MB-231, which shows constitutive activation of the NF-κβ program.
They transfected MDA-MB-231 cells with a lentivirus vector containing either microRNA-146a or microRNA-146b. Analysis confirmed that these cells showed 10- and 30-fold cytoplasmic elevation of these microRNA species relative to the low endogenous levels found in non-infected control cells.
Scott et al found that phosphorylation of Iκβa, a key measure of NF-κβ activation, was reduced 40% and 20% in microRNA-146a- and microRNA-146b-overexpressing cells, respectively, relative to control levels.
Crucially, these cells also showed a respective 25% and 20% reduction in invasion capacity and a 45% and 38% reduction in migration capacity relative to control cells.
Scott et al conclude: "Future studies evaluating the susceptibility of various other cancer cell lines and tumors with constitutively active NF-κβ programs to modulation by microRNA-146a/b expression will likely provide deeper insights and therapeutic opportunities for treating metastatic disease, a problem that has remained largely intractable."
Oncogene 2008; Advance online publication
http://www.nature.com/onc/index.html
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