Breast cancer is a common and aggressive cancer among women. Mortality is often caused by metastatic disease, but therapeutic options for treating metastases are limited. Signaling mediated by the transforming growth factor–β (TGF-β) and mitogen-activated protein kinase (MAPK) pathways are commonly associated with metastatic progression, and the abundance of the ubiquitin-conjugating enzyme Ubc13 is increased in metastatic breast cancer. Wu et al. explored the role of Ubc13 and its links with the TGF-β and MAPK pathways in breast cancer. In multiple xenograft or allograft models, knocking down Ubc13 before injection of the cells into the mammary fat pads of mice did not affect primary tumor growth but prevented or reduced the size and number of lung metastases. Bioluminescent imaging of breast cancer cells transfected with an inducible, fluorescent-labeled shRNA lentivirus against Ubc13 mRNA showed that Ubc13 was required for metastatic growth in the lung but not for extravasation or colonization of the secondary site. Compared with metastatic cells transfected with control shRNA, lung nodules formed by cells transfected with Ubc13-targeted shRNA had decreased abundance of Ki-67 (a proliferative marker) and increased abundance of cleaved caspase-3 (an apoptotic marker). TGF-β signaling is mediated through several pathways, some of which are mediated by transcriptional regulators known as SMADS. In cells cultured with TGF-β and in LM2 xenografts and lung metastases from the LM2 xenografrs, knocking down Ubc13 had no effect on the phosphorylation of SMADs (an indication of activation) but inhibited the phosphorylation of p38α (MAPK14) and TGF-β-activated kinase 1 (TAK1). Silencing p38α or TAK1 in cells prior to injection into the tail vein reduced the number of lung nodules formed, and injection of a pharmacological inhibitor of p38α into the circulation reduced the number of lung nodules in mice with established metastases. Overexpression of a constitutively active MAPK kinase 3 (MKK3), which mediates the activation of p38α downstream of TAK1, resulted in lung metastasis of Ubc13-deficient cells without affecting the mass of the primary tumor. Microarray analysis in a human breast cancer cell line showed that a previously reported metastatic gene signature was promoted by Ubc13 through MKK3and p38α, and bioinformatics analysis of human tissue correlated increased Ubc13 or p38α with poor patient survival. The findings suggest that Ubc13 promotes metastatic disease through SMAD-independent TGF-β signaling, and that a p38α inhibitor might be a therapeutic option for metastatic patients.
X. Wu, W. Zhang, J. Font-Burgada, T. Palmer, A. S. Hamil, S. K. Biswas, M. Poidinger, N. Borcherding, Q. Xie, L. G. Ellies, N. K. Lytle, L.-W. Wu, R. G. Fox, J. Yang, S. F. Dowdy, T. Reya, M. Karin, Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc. Natl. Acad. Sci. USA 111, 13870–13875 (2014). [Abstract] [Full text]