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Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.

ABSTRACT: 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 ? (TGF?)-induced SMAD activation but was required for activation of non-SMAD signaling via TGF?-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.

SUBMITTER: Wu X 

PROVIDER: S-EPMC4183333 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.

Wu Xuefeng X   Zhang Weizhou W   Font-Burgada Joan J   Palmer Trenis T   Hamil Alexander S AS   Biswas Subhra K SK   Poidinger Michael M   Borcherding Nicholas N   Xie Qing Q   Ellies Lesley G LG   Lytle Nikki K NK   Wu Li-Wha LW   Fox Raymond G RG   Yang Jing J   Dowdy Steven F SF   Reya Tannishtha T   Karin Michael M  

Proceedings of the National Academy of Sciences of the United States of America 20140904 38

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 fac  ...[more]

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