Abstract 3032: Tazarotene-induced gene 1 promotes tumorigenicity and invasiveness of inflammatory breast cancer through receptor tyrosine kinase Axl.
Authors: Wang Xiaoping , Saso Hitomi , Iwamoto Takayuki , Xia Weiya , Gong Yun , Pusztai Lajos , Woodward Wendy , Reuben James M. , Hortobagyi Gabriel N. , Hung Mien-Chie , Ueno Naoto T. 
Published: August 2014

Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer and is highly metastatic. The prognosis of patients with IBC is poor, and effective standard therapies for IBC are limited because the molecular mechanisms underlying the pathogenesis of IBC remain unknown. Therefore, there is an urgent need to identify novel molecules that are responsible for the aggressiveness of IBC and to elucidate the molecular mechanisms involved in tumorigenesis and metastasis of IBC. Such work may lead to early IBC diagnosis and new targeted therapies for IBC.

We recently found that tazarotene-induced gene 1 (TIG1) expression is significantly higher in IBC cell lines than in non-IBC cell lines. In both IBC and non-IBC data sets, estrogen receptor-negative/HER2-negative samples had significantly higher expression of TIG1 than did other clinical subtypes (estrogen receptor-positive/HER2-negative and HER2-positive). Therefore, we hypothesized that TIG1 plays an important role in the malignant process of IBC. In these studies, we determined the biological function of TIG1 in IBC cells and elucidated the molecular mechanism by which TIG1 regulates the invasiveness of IBC cells.

Our data show that high expression of TIG1 significantly correlated with shorter survival of patients with IBC . Knockdown of TIG1 expression in IBC cells reduced their proliferation, migration, and invasion in vitro. Also, silencing of TIG1 dramatically inhibited IBC tumor growth in a xenograft model. Moreover, restoring TIG1 expression rescued the proliferation, motility, and invasiveness of TIG1-silenced IBC cells. Most importantly, we identified Axl as a functional partner of TIG1 by showing that Axl expression positively correlated with TIG1 expression in IBC human tissues and TIG1 interacted with and stabilized Axl in IBC cells. TIG1 regulated the invasiveness of IBC cells through mediation of the Axl signaling pathway. In SUM149 cells, TIG1 depletion decreased Axl expression, which led to downregulation of expression of matrix metalloproteinase-9, a molecule required for Axl-mediated invasion, and inactivation of nuclear factor-κB, ultimately leading to decreased invasiveness of IBC cells.

In summary, our results identified TIG1 as an oncogenic gene that contributes to the tumorigenic and metastatic properties of IBC. Our data also linked TIG1 with the key tumorigenic gene Axl in IBC cells. Further studies are needed to confirm that TIG1 is a promising IBC-specific therapeutic target in the treatment of patients with IBC.

Citation Format: Xiaoping Wang, Hitomi Saso, Takayuki Iwamoto, Weiya Xia, Yun Gong, Lajos Pusztai, Wendy Woodward, James M. Reuben, Gabriel N. Hortobagyi, Mien-Chie Hung, Naoto T. Ueno. Tazarotene-induced gene 1 promotes tumorigenicity and invasiveness of inflammatory breast cancer through receptor tyrosine kinase Axl. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3032. doi:10.1158/1538-7445.AM2013-3032