TIG1 Promotes the Development and Progression of Inflammatory Breast Cancer through Activation of Axl Kinase
Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer inflammatoire du sein, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Axl, le gène TIG1 favorise l'agressivité de la maladie
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer, but the basis for its aggressive properties are not fully understood. In this study, we report that high tumoral expression of TIG1 (RARRES1), a functionally undefined membrane protein, confers shorter survival in IBC patients. TIG1 depletion decreased IBC cell proliferation, migration and invasion in vitro and inhibited tumor growth of IBC cells in vivo. We identified the receptor tyrosine kinase Axl as a TIG1 binding protein. TIG1 interaction stablilized Axl by inhibiting its proteasome-dependent degradation. TIG1-depleted IBC cells exhibited reduced Axl expression, inactivation of NF-κB and downregulation of MMP-9, indicating that TIG1 regulates invasion of IBC cells by supporting the Axl signaling pathway in IBC cells. Consistent with these results, treatment of IBC cells with the Axl inhibitor SGI-7079 decreased their malignant properties in vitro. Lastly, TIG1 expression correlated positively with Axl expression in primary human IBC specimens. Our findings establish that TIG1 positively modifies the malignant properties of IBC by supporting Axl function, advancing understanding of its development and rationalizing TIG1 and Axl as promising therapeutic targets in IBC treatment.