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  • Original Paper
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Tweak induces mammary epithelial branching morphogenesis

Oncogene volume 24, pages 2613–2624 (2005)Cite this article

Abstract

Members of the tumor necrosis factor (TNF) superfamily regulate cell survival and proliferation and have been implicated in cancer. Tweak (TNF-related weak inducer of apoptosis) has pleiotropic biological functions including proapoptotic, proangiogenic and proinflammatory activities. We explored a role for Tweak in mammary gland transformation using a three-dimensional model culture system. Tweak stimulates a branching morphogenic phenotype, similar to that induced by pro-oncogenic factors, in Eph4 mammary epithelial cells cultured in matrigel. Increased proliferation and invasiveness are observed, with a concomitant inhibition of functional differentiation. Levels of matrix metalloproteinase-9 (MMP-9) are significantly increased following Tweak treatment. Notably, MMP inhibitors are sufficient to block the branching phenotype induced by Tweak. The capacity to promote proliferation, inhibit differentiation and induce invasion suggests a role for Tweak in mammary gland tumorigenesis. Consistent with this, we have observed elevated protein levels of the Tweak receptor, Fn14, in human breast tumor cell lines and xenograft models as well as in primary human breast tumors. Together, our results suggest that the Tweak/Fn14 pathway may be protumorigenic in human breast cancer.

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Acknowledgements

We thank Tom Crowell for his adeptness in histological sample preparation and Humphrey Gardner, MD for his pathology expertise.

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Authors and Affiliations

  1. Department of Exploratory Science, Biogen Idec, 12 Cambridge Center, Bio6-320, Cambridge, MA, USA

    Jennifer S Michaelson, Sandy Cho, Beth Browning, Timothy S Zheng & Linda C Burkly

  2. Department of Transcript Profiling, Biogen Idec, 12 Cambridge Center, Cambridge, MA, USA

    John M Lincecum & Monica Z Wang

  3. Department of Protein Chemistry, Biogen Idec, 12 Cambridge Center, Cambridge, MA, USA

    Yen-Ming Hsu

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  1. Jennifer S Michaelson
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  2. Sandy Cho
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Correspondence to Jennifer S Michaelson.

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Michaelson, J., Cho, S., Browning, B. et al. Tweak induces mammary epithelial branching morphogenesis. Oncogene 24, 2613–2624 (2005). https://doi.org/10.1038/sj.onc.1208208

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