Abstract 172: BCL11A regulation of extracellular matrix genes may be necessary for invasion of triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) represents 15% of all breast cancers, yet conveys the poorest patient prognoses due to the lack of targeted therapies and the high incidence of metastatic recurrence. This prompt recurrence is thought to be due, in part, to the high proportion of cancer stem cells (CSC) within TNBC tumors. Therefore, understanding what regulates CSCs and metastasis will allow us to significantly reduce cancer-related deaths. One of the transcription factors that is upregulated in TNBC is BCL11A, which is critical for CSC biology. We have found that BCL11A is necessary for TNBC invasion and metastasis. However, the genes that BCL11A targets to control invasion and metastasis are unknown. To identify the BCL11A-regulated transcriptome, we performed RNA-seq analysis of MDA-MD-231 TNBC cells transiently transfected with BCL11A-targeted siRNA or a non-silencing control. Gene set enrichment analysis of the differentially expressed genes revealed enrichment of genes involved in extracellular matrix and matrisome genes. Notably, BCL11A silencing reduced expression of several matrix-metalloproteases, with MMP1 being the most significantly differentially expressed gene. Thus, we hypothesize that BCL11A promotes TNBC invasiveness and metastasis through regulation of MMP expression. We confirmed downregulation of MMP1 and MMP9 mRNA and protein in response to BCL11A silencing by both qRT-PCR and western blot in independent MDA-MB-231 cells, as well as in the HCC1143 TNBC cell line. MMP activity was also reduced when assessed by fluorokine assay and gelatin zymography, for MMP1 and MMP9, respectively. Furthermore, both BCL11A and MMP expression is increased in brain-seeking clones of MDA-MB-231 cells and MMP1 and 9 expression is also reduced with BCL11A silencing. Together, these data suggest that BCL11A regulates TNBC invasion by reducing the expression of MMP1 and MMP9. Current studies are directly assessing the functional impact of MMP regulation by BCL11A on invasion and metastatic progression of TNBC. Citation Format: Natasha N. Ingles, Darcie Seachrist, Ruth Keri. BCL11A regulation of extracellular matrix genes may be necessary for invasion of triple-negative breast cancer [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 172.