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. Here, 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 promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which 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.
Highlights
The phenotypes of each breast cancer subtype are defined by their transcriptomes
Consistent with prior reports, we found that Bcell leukemia/lymphoma 11A (BCL11A) expression is highly upregulated in basal breast cancer compared with the more differentiated luminal tumors in a publicly available data set [24] (Fig. 1A, left)
Because increased stem cell activity can promote metastatic disease in various cancers, we postulated that BCL11A is essential for breast cancer metastasis
Summary
The phenotypes of each breast cancer subtype are defined by their transcriptomes. the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor Bcell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis This increases the levels of an alternatively spliced isoform of integrin-a6 (ITGA6), which is associated with worse patient outcomes. BCL11A silencing reduces the TIC population in TNBC xenografts, and ectopic BCL11A expression in nontransformed immortalized mammary epithelial cells can promote xenograft tumor formation [14, 21] Whereas these studies have implicated BCL11A as a key driver of stem cell fate in the mammary epithelium that controls primary tumor growth, it is unknown whether this factor contributes to metastatic progression. Elucidation of the BCL11A-regulated transcriptome, followed by genetic modulation studies, further revealed that BCL11A is necessary for sustained expression of extracellular matrix and adhesion genes as well as the RNA splicing regulator, muscleblind-like protein 1 (MBNL1), and its downstream targets
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