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Page 2 of 7 Meng et al. J Cancer Metastasis Treat 2019;5:21 I http://dx.doi.org/10.20517/2394-4722.2018.96
[4]
subsequent implantation and proliferation in sites other than the primary location . Although we have
gained ample knowledge in this cellular process, an in-depth understanding at the molecular level remains
to be deciphered.

Alternative splicing might be such a molecular mechanism that contributes to metastasis. It is a process
whereby multiple functionally distinct transcripts are encoded from a single gene by the selective removal
or retention of exons and/or introns from the maturing RNA. This process is highly regulated, involving
trans-acting splicing factors and cis-acting regulatory motifs and so is susceptible to hereditary and
somatic mutations. Alternative splicing is common in many eukaryote lineages. Using deep transcriptome
sequencing of the human genome, over 95% of multi-exon genes were found capable of producing at least
[5]
one alternatively spliced isoform . Many single-gene studies have also characterized the role of alternative
splicing in various cellular processes. Disruption or dysregulation of alternative splicing has also been
[6,7]
[8]
associated with pathological states . Maguire et al. demonstrated that spliceosomal mutations occur in a
mutually exclusive manner in breast cancer and that distinct components of the spliceosome are targeted by
somatic mutations in different types of breast cancer. The exact splicing pattern associated with a particular
breast cancer type or stage still requires a broad characterization through molecular analysis of splicing
isoforms in different patients. However, existing evidence strongly supports a pivotal role of alternative
splicing in breast cancer biology and innovative tools are under development to use splicing events for
[10]
[9]
diagnostic and therapeutic purposes . Shapiro et al. observed an epithelial-mesenchymal transition
(EMT)-associated global change in alternative splicing of a number of genes that are involved in functions
crucial for EMT progression, such as cell adhesion, cell motility, and cytoskeletal remodeling. Several of the
splicing changes discovered in vitro were also found to occur in a panel of breast cancer cell lines and in
vivo in primary human breast cancer samples. Dysregulation of alternative splicing has been increasingly
recognized in cancer-related pathways. It is thus critical to investigate the functional significance of splicing
regulation in the context of cancer. This review will discuss some recent progresses about the alternative
splicing regulators such as CD44, heterogeneous nuclear ribonucleoprotein M (hnRNPM), SND1 and
MTDH etc. in breast cancer metastasis.

SPLICING VARIANTS MAY ENHANCE EMT AND METASTASIS IN BREAST CANCER
[12]
Dorman et al. reported splicing defects in large-scale breast cancer sequencing studies. Nine hundred
and eighty-eight splicing variants including exon skipping, leaky or cryptic splicing from 5,206 putative
mutations were confirmed for splicing mutations in 442 Breast Cancer patients from The Cancer Genome
Atlas dataset. These splicing variants were significantly increased in patients with lymph node metastasis, but
[13]
not in lymph node-negative tumors. Silipo et al. reported that the expression profile changes of splicing
factors including serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, SRSF3, SRSF5, SRSF6 and SRSF10;
the heterogeneous nuclear ribonucleoproteins (hnRNPs) including hnRNP A2/B1, hnRNPI, hnRNPA1 and
hnRNP K; as well as eight RNA-binding proteins including HuR, Sam68, BRM5, FOX2, YB-1, PRMT6,
SPF45 and PELP1 in breast cancer cells compared with normal cells, which are strongly associated with the
alternative splicing pattern of many cancer-related genes despite the absence of mutations in genomic DNA.
[14]
Inoue et al. reported aberrant splicing of CD44 gene in breast cancer, which promotes metastasis. The
status of splicing factors and other splicing-related proteins in breast cancer are important to provide insights
[15]
into the mechanisms that lead to breast cancer metastasis . The correlation analysis of somatic variants
with alternative splicing events confirmed known trans- associations with variants in SF3B1 and U2AF1,
and additional trans-acting variants (e.g., TADA1, PPP2R1A). Tumors have up to 30% more alternative
splicing events than normal samples. Many tumors have thousands of alternative splicing events that are
not detectable in normal samples. On average, 930 exon-exon junctions (‘‘neojunctions’’) were identified in
[15]
tumors not typically found in normal tissue included in the Genotype-Tissue Expression (GTEx) project .
CD44 is a cell surface protein with various isoforms that involves in motility, cell survival and proliferation