Abstract P5-05-05: Tazarotene-Induced Gene 1(TIG1) Is a Novel Tumorigenic Gene of Inflammatory Breast Cancer

Abstract

Abstract Background: Inflammatory breast cancer (IBC) is the most lethal and aggressive form of advanced breast cancer. Effective standard therapies for IBC are limited and the molecular mechanisms underlying IBC are largely unknown. In a comparison of samples from patients with IBC and non-IBC, our laboratory identified TIG1 (tazarotene-induced gene 1), also known as retinoic acid receptor responder 1 (RARRES1) as the gene with the largest difference in expression between the two groups. TIG1 is specifically expressed in IBC cell lines (SUM149 and KPL-4). In addition, TIG1 has been identified as a top druggable gene for triple-negative breast cancer. Of particular interest is that TIG1 is significantly expressed in IBC ER-/HER2- patient samples when compared with non-IBC ER-/HER2- patient samples (p = 0.084).Therefore, we hypothesize that TIG1 plays an important role in the malignant process of IBC and it promotes the tumorigenesis and metastasis of IBC. In these studies we determined the tumorigenic and metastatic activities of TIG1 in IBC. Methods: TIG1 was stably knocked down in the highly TIG1-expressing IBC cell line SUM149 and the effects of knockdown on cell proliferation, migration, invasion, and growth in three-dimensional culture were analyzed in vitro. To evaluate the tumorigenic activity of TIG1 in vivo, TIG1 stable-knockdown SUM149 cells and control shRNA-transfected cells were implanted into the mammary fat pads of athymic nude mice, and tumor growth was monitored. To investigate the underlying mechanism of TIG1- mediated tumorigenesis and metastasis of IBC, the gene expression profiles of control siRNA-transfected and TIG1 siRNA-transfected SUM149 cells were compared using cDNA microarray analysis. Results: Suppressing TIG1 significantly inhibited the proliferation, migration, and invasion of IBC cells in vitro. SUM149 cells exhibit a mesenchymal-like phenotype when grown in three-dimensional culture. However, knocking down TIG1 reversed the mesenchymal-like phenotype to the epithelial phenotype in three-dimensional culture, suggesting that TIG1 might have metastatic activity in IBC cells. TIG1 knockdown dramatically inhibited IBC tumor growth in a xenograft model. Several differentially expressed genes between control siRNA-transfected and TIG1 siRNA-transfected SUM149 cells, including Decorin, GBP1, and VAV3 were identified using cDNA microarray analysis. These genes have been reported to affect a number of biological processes, including proliferation, metastasis, inflammatory response, and angiogenesis. We will focus on these candidates and determine the molecular mechanism by which TIG1 may function as a tumorigenic gene in IBC. Conclusion: Our data demonstrate that TIG1 promotes the tumorigenesis and metastasis of IBC and it may contribute to the development and aggressiveness of IBC. Our long-term goal is to develop TIG1 as a therapeutic target for this extremely aggressive type of breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-05.