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Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Sep 23; Vol. 111 (38), pp. 13870-5. Date of Electronic Publication: 2014 Sep 04. - Publication Year :
- 2014
-
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 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.
- Subjects :
- Animals
Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Line, Tumor
Female
Heterografts
Humans
MAP Kinase Kinase Kinases genetics
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Neoplasm Proteins genetics
Neoplasm Transplantation
Ubiquitin-Conjugating Enzymes genetics
p38 Mitogen-Activated Protein Kinases genetics
Breast Neoplasms enzymology
MAP Kinase Kinase Kinases metabolism
MAP Kinase Signaling System
Neoplasm Proteins metabolism
Ubiquitin-Conjugating Enzymes metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 25189770
- Full Text :
- https://doi.org/10.1073/pnas.1414358111