Tweak induces mammary epithelial branching morphogenesis.
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.
Michaelson
Jennifer S
JS
Department of Exploratory Science, Biogen Idec, 12 Cambridge Center, Bio6-320, Cambridge MA, USA. Jennifer.Michaelson@BiogenIdec.com
Cho
Sandy
S
Browning
Beth
B
Zheng
Timothy S
TS
Lincecum
John M
JM
Wang
Monica Z
MZ
Hsu
Yen-Ming
YM
Burkly
Linda C
LC
D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen; D000074049:Cytokine TWEAK; D004338:Drug Combinations; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin; D042361:Mammary Glands, Human / Q000166:cytology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008954:Models, Biological; D009024:Morphogenesis; D011509:Proteoglycans; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; C059485:matrigel; D003094:Collagen; D020780:Matrix Metalloproteinase 9