TGIF Governs a Feed-Forward Network that Empowers Wnt Signaling to Drive Mammary Tumorigenesis

Many types of human cancers having hyperactivated Wnt signaling display no causative alterations in known effectors of this pathway. Here, we report a function of TGIF in Wnt signaling. TGIF associates with and diverts Axin1 and Axin2 from the β-catenin destruction complex, therefore allowing β-cate...

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Published in:Cancer cell 2015-04, Vol.27 (4), p.547-560
Main Authors: Zhang, Ming-Zhu, Ferrigno, Olivier, Wang, Zhe, Ohnishi, Mutsuko, Prunier, Céline, Levy, Laurence, Razzaque, Mohammed, Horne, Williams C., Romero, Damian, Tzivion, Guri, Colland, Frédéric, Baron, Roland, Atfi, Azeddine
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Animals
Axin Protein - metabolism
beta Catenin - metabolism
Homeodomain Proteins - metabolism
Homeodomain Proteins - physiology
Humans
Mammary Neoplasms, Experimental - metabolism
Mice
Models, Biological
Repressor Proteins - metabolism
Repressor Proteins - physiology
Wnt Signaling Pathway
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Summary:Many types of human cancers having hyperactivated Wnt signaling display no causative alterations in known effectors of this pathway. Here, we report a function of TGIF in Wnt signaling. TGIF associates with and diverts Axin1 and Axin2 from the β-catenin destruction complex, therefore allowing β-catenin accrual. Intriguingly, activation of Wnt signaling induces the expression of TGIF, which unveils a feed-forward loop that ensures effective integration of Wnt signaling. In triple-negative breast cancers (TNBC), elevated levels of TGIF correlate with high Wnt signaling and poor survival of patients. Moreover, genetic experiments revealed that Tgif1 ablation impeded mammary tumor development in MMTV-Wnt1 mice, further underscoring a requirement of TGIF for oncogenic Wnt signaling. •TGIF functions as a mediator of Wnt/β-catenin signaling•The association of TGIF with Axin1 and Axin2 promotes β-catenin stability•TGIF1 is a Wnt target gene•TGIF is essential for Wnt-driven mammary tumorigenesis Zhang et al. show that TGIF interacts with Axin1 and Axin2, thus preventing them from translocating to cytoplasm to form the β-catenin destruction complex. A TGIF-Wnt feed-forward loop is important for mammary tumorigenesis induced by hyperactivated Wnt signaling.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2015.03.002