Abstract 32: BCL11A is necessary for the expression of extracellular matrix genes and metastatic progression of triple-negative breast cancer

Cancer stem cells (CSC) contribute to the high incidence of metastatic recurrence in triple-negative breast cancer (TNBC) and elucidating the mechanisms controlling CSC properties should provide novel targets for therapeutic development that improves patient outcomes. The transcription factor BCL11A is highly differentially expressed in TNBC versus all other subtypes and controls breast CSC phenotypes such as marker expression and tumor initiation. However, the genes that BCL11A targets to control CSC biology and whether BCL11A promotes metastatic progression are unknown. To address these questions, we assessed the impact of transiently silencing the expression of BCL11A in TNBC cells using siRNA transfections. Reducing BCL11A expression did not impact TNBC cell viability or in vitro migratory capacity. However, silencing BCL11A significantly decreased invasion of TNBC cell lines, in vitro. Furthermore, stable shRNA-mediated silencing of BCL11A in the highly metastatic MDA-MB-231 cell line reduced metastatic outgrowth when xenografted into immunocompromised mice, suggesting that BCL11A is critical for metastatic progression of TNBC. To identify the BCL11A-regulated transcriptome in TNBC, we performed RNA-seq analysis of cells transiently transfected with non-targeting or BCL11A-targeted siRNAs in the MDA-MB-231 cell line. Consistent with the impact of BCL11A on invasion, numerous genes involved in adhesion and extracellular matrix were reduced with BCL11A silencing. The gene encoding the matrix metalloproteinase, MMP1, was the most significantly differentially expressed gene, with a 10-fold decrease in RNA expression following BCL11A suppression. We confirmed this down-regulation by both qRT-PCR and western blots of independent samples, as well as in the HCC1143 TNBC cell line. Current studies are assessing the functional impact of MMP1 regulation by BCL11A on invasion and metastatic progression of TNBC. Citation Format: Darcie D. Seachrist, Natasha N. Ingles, Molly M. Hannigan, Donny D. Licatalosi, Ruth A. Keri. BCL11A is necessary for the expression of extracellular matrix genes and metastatic progression of triple-negative breast cancer [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 32.