Abstract 4626: TBX1 functions as a potential oncogene in breast cancer

Abstract

Abstract We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, to be associated with breast cancer risk in genome-wide association studies. This SNP is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. TBX1 is a member of the T-box transcription factor gene family, which plays important roles in embryogenesis and organogenesis. Previous studies have indicated that TBX1 exerted potential tumor suppressor functions in mouse skin tumors and human thyroid cancer. However, the biological functions and molecular mechanisms of TBX1 in breast cancer remain largely unknown. In this study, we investigated whether the association of the 22q11.21 locus with breast cancer risk was mediated by the TBX1 gene. Using The Cancer Genome Atlas (TCGA) data, we found that TBX1 expression was significantly upregulated in breast cancer tissues compared to adjacent normal breast tissues. To investigate the biological functions of the TBX1 gene in breast cancer, we knock-downed TBX1 gene expression using siRNAs in MDA-MB-231, MCF-7 and T47D breast cancer cell lines. Our results showed that knocking down TBX1 expression significantly inhibited breast cancer cell proliferation, migration and invasion. We further performed RNA sequencing in both TBX1 knocked-down and control MDA-MB-231 cells. Our differential gene expression and gene set enrichment analyses showed that knocked-down TBX1 expression significantly downregulated cell cycle-related genes, including CDC6, CDK6, DHFR, CIT, ORAI1 and TOP2A (P < 10−30). These six downregulated genes in TBX1 knocked-downed MDA-MB-231 cells were further confirmed by quantitative real-time PCR (qPCR). Furthermore, using the JASPAR database to predict TBX1 binding motif, we found that TBX1 may bind to the promoter regions of these six genes. In summary, our results suggest that TBX1 acts as a potential oncogene in breast cancer through regulating the expression of cell cycle-related genes, and the associations between genetic variants in the 22q11.21 locus and breast cancer risk may be mediated through altered expression of the TBX1 gene. Citation Format: Shuya Huang, Xiang Shu, Jie Wu, Jifeng Wang, Xingyi Guo, Jie Ping, Joshua A. Bauer, Jirong Long, Xiao-Ou Shu, Wei Zheng, Qiuyin Cai. TBX1 functions as a potential oncogene in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4626.