Abstract 5313: Frequent downregulation of SALL3 by genetic and epigenetic alterations is involved in progression and chemoresistance of triple negative breast cancers

Abstract

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer and worse disease-specific outcomes compared with other subtypes. Because of the lack of estrogen and progesterone receptors and HER2 gene amplification, cytotoxic agents remain the mainstay of treatment for TNBC patients. Although TNBC is enriched for germline and somatic BRCA mutation, a phenotype termed BRCAness, PARP inhibitors as monotherapy failed to improve the outcome of TNBC patients. Therefore, we aimed to uncover molecular characterization 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. 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, promoter regions of SALL3 gene was frequently hypermethylated and transcriptionally silenced in only TNBC cases, but not in other types of breast cancer by TCGA data analysis. Moreover, the expression of SALL3 was restored after treatments of 5-aza-2’-deoxycitidine 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. Notably, because SALL3 retains eight C2H2-type zinc finger domains which are extremely conserved in mammalian transcription factors, we hypothesized that SALL3 transcriptionally regulates genes which are involved in progression and chemoresistance of TNBC. We identified the several candidates of SALL3-taget genes by gene expression and chromatin immunoprecipitation analyses. Our findings provide the evidence of a pathophysiological role for SALL3 as a tumor suppressor which is possibly associated with progression and chemoresistance of TNBC. Citation Format: Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri. Frequent downregulation of SALL3 by genetic and epigenetic alterations is involved in progression and chemoresistance of triple negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5313.