Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc Natl Acad Sci U S A 2014 Sep 23;111(38):13870-5
Date
09/06/2014Pubmed ID
25189770Pubmed Central ID
PMC4183333DOI
10.1073/pnas.1414358111Scopus ID
2-s2.0-84907284168 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
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.
Author List
Wu X, Zhang W, Font-Burgada J, Palmer T, Hamil AS, Biswas SK, Poidinger M, Borcherding N, Xie Q, Ellies LG, Lytle NK, Wu LW, Fox RG, Yang J, Dowdy SF, Reya T, Karin MAuthor
Nikki K. Lytle PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBreast Neoplasms
Cell Line, Tumor
Female
Heterografts
Humans
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Metastasis
Neoplasm Proteins
Neoplasm Transplantation
Ubiquitin-Conjugating Enzymes
p38 Mitogen-Activated Protein Kinases
