The transcriptional repressor BCL11A promotes breast cancer metastasis

Abstract

The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Herein, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A), is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promoted cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), encoding a splicing regulator that suppresses metastasis. This ultimately increased the levels of an alternatively spliced isoform of integrin-α6 (ITGA6) that is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6. Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.

Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

“…In contrast, Bcl11a expression was elevated by an average of 2.1-fold ( p = 0.00001) in samples with SB insertions targeting this gene. This is consistent with the transforming effect of Bcl11a when overexpressed 42 . We next tested for a link between gCIS-expression and tumor histology.…”

Hypoxia-Associated Prognostic Markers and Competing Endogenous RNA Co-Expression Networks in Breast Cancer

“…Besides, by directly interacting with the 3'UTR of Bcl2, miR-190b induces osteosarcoma cell apoptosis and confers radio-sensitivity to gastric cancer cells (58,59). According to reports, BCL11A acts as a carcinogenic gene for a variety of human cancers, such as breast cancer (60) proliferation and migration ability in the pathogenesis of breast cancer (64).…”

“…Besides, by directly interacting with the 3’UTR of Bcl2, miR-190b induces osteosarcoma cell apoptosis and confers radio-sensitivity to gastric cancer cells ( 58 , 59 ). According to reports, BCL11A acts as a carcinogenic gene for a variety of human cancers, such as breast cancer ( 60 ), laryngeal squamous cell carcinoma ( 61 ), high-risk neuroblastoma ( 62 ), non-small cell lung cancer ( 63 ) etc. In addition, the expression of PSMG3-AS1 in breast cancer tumor tissues and cell lines was increased, and PSMG3-AS1 as a sponge of miR-143-3p enhanced the proliferation and migration ability in the pathogenesis of breast cancer ( 64 ).…”

Identification and Interaction Analysis of Molecular Markers in Pancreatic Ductal Adenocarcinoma by Integrated Bioinformatics Analysis and Molecular Docking Experiments

“…Jung et al [105] found that SMPD1 stimulates the drug resistance in colorectal cancer, but this gene might be linked with development of PDAC. Liu et al [106], Yang et al [107], Song et al [108], Seachrist et al [109], Zhu et al [110], Wu et al [111], Wang et al [112], Yi et al [113], Lan et al [114] and Appert-Collin et al [115] revealed that PADI4, MAOB (monoamine oxidase B), TRPC6, BCL11A, CXCR5, TCF7, POU2F2, SLC4A1, STK17B and LRP1 were associated with cancer cell invasion, but these genes might be liable for progression of PDAC. Kairouz et al [116], Diez-Bello et al [117], Xue et al [118], Abo-Elfadl et al [119], Li et al [120] and Zhao et al [121] reported that GRB14, TRPC6, ZFPM2, TNFRSF13B, ADAM19 and PIK3IP1enhance the cancer cell proliferation, but this gene might be involved in advancement of PDAC.…”