Abstract
It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteins with pro-cancer properties. These changes in alternative splicing can arise from mutations or single-nucleotide polymorphisms (SNPs) within the DNA sequences of cancer-related genes, which can strongly affect the activity of splicing factors and influence the splice site choice. However, it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection. There is now increasing evidence to demonstrate that the expression profile of ten splicing factors (including SRs and hnRNPs) and eight RNA-binding proteins changes in breast cancer cells compared with normal cells. These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences. Thus, a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis. Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes, this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.
Highlights
The majority of human protein-coding genes produce multiple mRNA transcripts by alternative splicing
Summary This review has focused on SRs, hnRNPs and other RNA-binding proteins that are themselves deregulated in breast cancer, including genes classified as either proto-oncogenes (e.g. SRSF1, SRFS3, DAM1, PELP1) or tumour suppressors (e.g. RBM, PRMT6)
The advent of high throughput systems such as LISA - a high-throughput reverse transcription-PCR-based platform – provide a means to reveal hundreds of cancer-associated alternative splicing events in different cancers including breast (Klinck et al, 2008; Venables et al, 2008a); this experimental approach can be exploited by combining RNAi with LISA to work out how splicing factors affect subsets of genes in different cellular contexts (Venables et al, 2008)
Summary
The majority of human protein-coding genes produce multiple mRNA transcripts by alternative splicing. Overexpression of SRSF1 regulates the inclusion of an exclusive exon 13b of the MKNK2 gene promoting production of the Mnk2b splice variant (Karni et al, 2007).
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