Abstract 5315: Frequent downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple-negative breast cancers

Abstract

Abstract Triple negative breast cancers (TNBC), defined by the lack of estrogen and progesterone receptors and HER2 gene amplification, is a heterogeneous and clinically aggressive disease due to the lack of beneficial therapeutic targets. Even though one of the most major risk for the development of TNBC is carrying a deleterious germline and somatic mutations of BRCA1 are not frequently found in sporadic cases of TNBC. Therefore, we aimed to search genomic alterations in TNBC cases by whole-exome sequencing analysis of genomic DNAs from 36 Japanese patients with TNBC compared with their corresponding normal. We identified 36 genes that were recurrently mutated (>10% of cases) in TNBC cases, including TP53 and PIK3CA as described in the previous next generation sequencing analysis of TNBC cases. Remarkably, we identified a number of epigenetic-related genes involved in histone modification and DNA methylation, which were mutated in 20 out of 36 (55.6%) cases. Among them, we focused on spalt like transcription factor 3 (SALL3) gene which shows recurrent somatic mutations, and are most frequently downregulated in TNBC cases. Nonsense-mutation of SALL3 (E169X) completely abolish its binding to DNAMT3A. Ectopic overexpression of the wildtype SALL3, but not the somatically mutated SALL3 into BT549 breast cancer cells, which expresses low level of SALL3 gene, caused the significant suppression of cell growth. Importantly, SALL3 gene was frequently hypermethylated and transcriptionally silenced in only TNBC cases, but not in other types of breast cancer using TCGA data sets. Moreover, the expression of SALL3 was restored after treatments of 5-aza-2'-deoxycitidine (5-aza-dC) in TNBC cell line, HCC1937. Notably, siRNA-mediated knockdown of SALL3 expression in BT20 cells enhanced chemoresistance against paclitaxel and docetaxel, respectively. Moreover, low expression of SALL3 was associated with significantly shorter relapse free survival. Our findings provide the evidence of a pathophysiological role for SALL3 as a tumor suppressor which is possibly associated with carcinogenesis for TNBC. Citation Format: Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri. Frequent downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5315.