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Wu, Xuefeng; Zhang, Weizhou; Font-Burgada, Joan; Palmer, Trenis; Hamil, Alexander S.; Biswas, Subhra K.; Poidinger, Michael; Borcherding, Nicholas; Xie, Qing; Ellies, Lesley G.; Lytle, Nikki K.; Wu, Li-Wha; Fox, Raymond G.; Yang, Jing; Dowdy, Steven F.; Reya, Tannishtha; Karin, Michael
Proceedings of the National Academy of Sciences, 09/2014, Letnik: 111, Številka: 38Journal Article
Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa. Significance We demonstrate that ubiquitin-conjugating enzyme Ubc13, whose expression is elevated in primary and metastatic breast cancer (BCa), promotes metastatic spread of BCa cells by controlling their lung-colonizing ability while having little effect on primary tumor growth. Mechanistically, Ubc13 is required for TGFβ-induced non-SMAD signaling via TAK1 and p38, a pathway that is first activated in the primary tumor. An Ubc13- and p38-dependent metastatic gene signature was identified, explaining how p38 may control metastasis and providing a measure for monitoring the effectiveness of pharmacologic p38 inhibition, which inhibits the growth of established metastatic lesions. We suggest that p38 inhibition should be considered as a potential treatment for metastatic BCa.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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