1. ¹Department of Exploratory Science, Biogen Idec, 12 Cambridge Center, Bio6-320, Cambridge MA, USA
2. ²Department of Transcript Profiling, Biogen Idec, 12 Cambridge Center, Cambridge MA, USA
3. ³Department of Protein Chemistry, Biogen Idec, 12 Cambridge Center, Cambridge MA, USA

Correspondence: JS Michaelson, E-mail: Jennifer.Michaelson@BiogenIdec.com

Received 15 June 2004; Revised 31 August 2004; Accepted 16 September 2004; Published online 21 February 2005.

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.