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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References
Barsky SH, Togo S, Garbisa S and Liotta LA . (1983). Lancet, 1, 296–297.
Bond M, Fabunmi RP, Baker AH and Newby AC . (1998). FEBS Lett., 435, 29–34.
Brinkmann V, Foroutan H, Sachs M, Weidner KM and Birchmeier W . (1995). J. Cell Biol., 131, 1573–1586.
Brown SA, Richards CM, Hanscom HN, Feng SL and Winkles JA . (2003). Biochem. J., 371, 395–403.
Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I and Browning JL . (1997). J. Biol. Chem., 272, 32401–32410.
Chicheportiche Y, Chicheportiche R, Sizing I, Thompson J, Benjamin CB, Ambrose C and Dayer JM . (2002). Arthritis Res., 4, 126–133.
Dranoff G . (2004). Nat. Rev., 4, 11–22.
Duffy MJ, Maguire TM, Hill A, McDermott E and O'Higgins N . (2000). Breast Cancer Res., 2, 252–257.
Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, Peifley KA and Winkles JA . (2000). Am. J. Path., 156, 1253–1261.
Gaide O and Schneider P . (2003). Nat. Med., 9, 614–618.
Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB and Von Hoff DD . (2002). Cancer Res., 62, 2890–2896.
Harada N, Nakayama M, Nakano H, Fukuchi Y, Yagita H and Okumura K . (2002). Biochem. Biophys. Res. Comm., 299, 488–493.
Ip MM, Shoemaker SF and Darcy KM . (1992). Endocrinology, 130, 2833–2844.
Jakubowski A, Browning B, Lukashev M, Sizing I, Thompson JS, Benjamin CD, Hsu YM, Ambrose C, Zheng TS and Burkly LC . (2002). J. Cell Sci., 115, 267–274.
Janda E, Litos G, Grunert S, Downward J and Beug H . (2002). Oncogene, 21, 5148–5159.
Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J and Farrow SN . (2000). FEBS Lett., 485, 135–141.
Kessler D, Dethlefsen S, Haase I, Plomann M, Hirche F, Krieg T and Eckes B . (2001). J. Biol. Chem., 276, 36575–36585.
Lee PP, Hwang JJ, Mead L and Ip MM . (2001). J. Cell. Physiol., 188, 75–88.
Lee PP, Hwang JJ, Murphy G and Ip MM . (2000). Endocrinology, 141, 3764–3773.
Logarajah S, Hunter P, Kraman M, Steele D, Lakhani S, Bobrow L, Venkitaraman A and Wagner S . (2003). Oncogene, 22, 5572–5578.
Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA and Wiley SR . (1999). J. Biol. Chem., 274, 8455–8459.
Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR, Berens T, Coons SW, Watts G, Trent JM, Wei JS, Giese A and Berens ME . (2001). J. Neurooncol., 53, 161–176.
Michaelson JS and Leder P . (2001). Oncogene, 20, 5093–5099.
Nakayama M, Harada N, Okumura K and Yagita H . (2003). Biochem. Biophys. Res. Comm., 306, 819–825.
Nakayama M, Ishidoh K, Kayagaki N, Kojima Y, Yamaguchi N, Nakano H, Kominami E, Okumura K and Yagita H . (2002). J. Immunol., 168, 734–743.
Nakayama M, Kayagaki N, Yamaguchi N, Okumura K and Yagita H . (2000). J. Exp. Med., 192, 1373–1380.
Niemann C, Brinkmann V, Spitzer E, Hartmann G, Sachs M, Naundorf H and Birchmeier W . (1998). J. Cell Biol., 143, 533–545.
Pinkas J and Leder P . (2002). Cancer Res., 62, 4781–4790.
Reichmann E, Ball R, Groner B and Friis RR . (1989). J. Cell Biol., 108, 1127–1138.
Saas P, Boucraut J, Walker PR, Quiquerez AL, Billot M, Desplat-Jego S, Chicheportiche Y and Dietrich PY . (2000). Glia, 32, 102–107.
Saitoh T, Nakayama M, Nakano H, Yagita H, Yamamoto N and Yamaoka S . (2003). J. Cell Biol., 278, 36005–36012.
Schneider P, Schwenzer R, Haas E, Muhlenbeck F, Schubert G, Scheurich P, Tschopp J and Wajant H . (1999). Eur. J. Immunol., 29, 1785–1792.
Shea-Eaton WK, Lee PP and Ip MM . (2001). Endocrinology, 142, 2558–2568.
Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA and Merlino G . (1997). Proc. Natl. Acad. Sci. USA, 94, 701–706.
Tran NL, McDonough WS, Donohue PJ, Winkles JA, Berens TJ, Ross KR, Hoelzinger DB, Beaudry C, Coons SW and Berens ME . (2003). Am. J. Path., 162, 1313–1321.
Varela LM, Stangle-Castor NC, Shoemaker SF, Shea-Eaton WK and Ip MM . (2001). J. Cell Physiol., 188, 120–131.
Wechselberger C, Ebert AD, Bianco C, Khan NI, Sun Y, Wallace-Jones B, Montesano R and Salomon DS . (2001). Exp. Cell Res., 266, 95–105.
Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, Liu H, Daniel TO, Smith CA and Fanslow WC . (2001). Immunity, 15, 837–846.
Wiley SR and Winkles JA . (2003). Cytokine Growth Factor Rev., 14, 241–249.
Wilson CA and Browning JL . (2002). Cell Death Differ., 9, 1321–1333.
Younes A and Kadin ME . (2003). J. Clin. Oncol., 21, 3526–3534.
Acknowledgements
We thank Tom Crowell for his adeptness in histological sample preparation and Humphrey Gardner, MD for his pathology expertise.
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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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DOI: https://doi.org/10.1038/sj.onc.1208208
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