Upregulation of RPA2 promotes NF-κB activation in breast cancer by relieving the antagonistic function of menin on NF-κB-regulated transcription

<span class="paragraphSection"><div class="boxTitle">Abstract</div>RPA2, a subunit of the heterotrimeric replication protein A (RPA) complex, is overexpressed in various cancers. In this study, we showed a significant RPA2 upregulation in breast cancer tissues and cell lines. Ectopic expression of RPA2 in MCF7 and MDA-MB-231 cells promoted cell proliferation, adhesion, migration and invasion, and induced epithelial-mesenchymal transition (EMT) of MCF7 cells. Ablation of RPA2 in MDA-MB-231 cells induced apoptosis and suppressed colony formation, EMT and invasion. Binding assays indicated that menin, the multiple endocrine neoplasia type 1 (<span style="font-style:italic;">MEN1</span>) tumor suppressor gene product, interacted with RPA2. Ectopic expression of RPA2 inhibited the formation of the menin-NK-κB p65 complex and repressed the inhibitory effect of menin on expression of NF-κB-regulated genes that contribute to tumor progression. Conversely, knockdown of RPA2 promoted formation of the menin-p65 complex and repressed the expression of NF-κB-mediated genes. RPA2 expression was induced via an E2F1-dependent mechanism in MCF7 and MDA-MB-231 cells treated with NF-κB activators, TNF-alpha or lipopolysaccharide (LPS). These results suggested that RPA2-dependent tumorigenicity was mediated via enhancement of NF-κB activity by relieving the antagonistic function of menin on NF-κB-regulated transcription in breast cancer cells.</span>

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