Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 38, Pages 13870-13875Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1414358111
Keywords
ubiquitination-mediated signaling; pre-clinical studies
Categories
Funding
- Biomedical Research Council, A*STAR
- Susan G. Komen for the Cure [KG111506]
- National Institutes of Health (NIH) [1R01CA168689, 3R01CA168689-02W1, DP1CA174422, T32 CA009523-29, T32 GM007752-36]
- NIH [CA163798, AI043477]
- San Diego Cancer Center Council Collaborative Translational Grant - Pedal the Cause San Diego
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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 beta (TGF beta)-induced SMAD activation but was required for activation of non-SMAD signaling via TGF beta-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.
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