Contribution of alternative splicing to breast cancer metastasis

Abstract

Alternative splicing is a major contributor to transcriptome and proteome diversity in eukaryotes. Comparing to normal samples, about 30% more alternative splicing events were recently identified in 32 cancer types included in The Cancer Genome Atlas database. Some alternative splicing isoforms and their encoded proteins contribute to specific cancer hallmarks. In this review, we will discuss recent progress regarding the contributions of alternative splicing to breast cancer metastasis. We plan to dissect the role of MTDH, CD44 and their interaction with other mRNA splicing factors. We believe an in-depth understanding of the mechanism underlying the contribution of splicing to breast cancer metastasis will provide novel strategies to the management of breast cancer.

Keywords

Breast cancer / metastasis / CD44 / MTDH / splicing / epithelial-mesenchymal transition

References

[1] Mansoori B,Ghasabi M,Dehghan R.miR-142-3p as tumor suppressor miRNA in the regulation of tumorigenicity, invasion and migration of human breast cancer by targeting Bach-1 expression..J Cell Physiol2019;234:9816-25

[2] da Costa AM,Fregnani JHTG.Overall survival and time trends in breast and cervical cancer incidence and mortality in the Regional Health District (RHD) of Barretos, São Paulo, Brazil..BMC Cancer2018;18:1079 PMCID:PMC6223073

[3] Scully OJ,Yip G.Breast cancer metastasis..Cancer Genomics Proteomics2012;9:311-20

[4] Saharat K,Chokchaichamnankit D,Svasti J.Tumor susceptibility gene 101 mediates anoikis resistance of metastatic thyroid cancer cells..Cancer Genomics Proteomics2018;15:473-83 PMCID:PMC6299787

[5] Bush SJ,Tovar-Corona JM.Alternative splicing and the evolution of phenotypic novelty..Philos Trans R Soc Lond B Biol Sci2017;372:20150474 PMCID:PMC5182408

[6] Cieply B.Functional roles of alternative splicing factors in human disease..Wiley Interdiscip Rev RNA2015;6:311-26 PMCID:PMC4671264

[7] Orengo JP.Alternative splicing in disease..Adv Exp Med Biol2007;623:212-23

[8] Maguire SL,Wai P,Ng CK.SF3B1 mutations constitute a novel therapeutic target in breast cancer..J Pathol2015;235:571-80 PMCID:PMC4643177

[9] Martínez-Montiel N,Pérez-Santos M.Alternative splicing in breast cancer and the potential development of therapeutic tools..Genes (Basel)2017;8:217 PMCID:PMC5664086

[10] Shapiro IM,Flytzanis NC,Condeelis JS.An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype..PLoS Genet2011;7:e1002218 PMCID:PMC3158048

[11] Xu Y,Lee JH,Tan H.Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing..Genes Dev2014;28:1191-203 PMCID:PMC4052765

[12] Dorman SN,Rogan PK.Splicing mutation analysis reveals previously unrecognized pathways in lymph node-invasive breast cancer..Sci Rep2014;4:7063 PMCID:PMC4231324

[13] Silipo M,Tyson-Capper A.Deregulation of splicing factors and breast cancer development..J Mol Cell Biol2015;7:388-401

[14] Inoue K.Aberrant splicing of estrogen receptor, HER2, and CD44 genes in breast cancer..Genet Epigenet2015;7:19-32 PMCID:PMC4669075

[15] Kahles A,Toussaint NC,Stark SG.Comprehensive analysis of alternative splicing across tumors from 8,705 patients..Cancer Cell2018;34:211-24

[16] Ishimoto T,Yae T,Motohara T.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth..Cancer Cell2011;19:387-400

[17] Prochazka L,Turanek J.Regulation of alternative splicing of CD44 in cancer..Cell Signal2014;26:2234-9

[18] Xu Y,Lee JH,Tan H.Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing..Genes Dev2014;11:1191-203 PMCID:PMC4052765

[19] Harvey SE,Lin X,Qiu Y.Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT..RNA2018;24:1326-38 PMCID:PMC6140460

[20] Sun H,Zhu D,Liu F.HnRNPM and CD44s expression affects tumor aggressiveness and predicts poor prognosis in breast cancer with axillary lymph node metastases..Genes Chromosomes Cancer2017;56:598-607

[21] Zhang FL,Xie HY,Yang LF.Cancer-associated MORC2-mutant M276I regulates an hnRNPM-mediated CD44 splicing switch to promote invasion and metastasis in triple-negative breast cancer..Cancer Res2018;20:5780-92

[22] Ke H,Zhang H,Xu H.Loss of TDP43 inhibits progression of triple-negative breast cancer in coordination with SRSF3..Proc Natl Acad Sci U S A2018;115:E3426-35 PMCID:PMC5899436

[23] DeLigio JT,Chalfant CE.Splice variants of cytosolic polyadenylation element-binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis..J Biol Chem2017;292:17909-18 PMCID:PMC5663888

[24] Fici P,Morel AP,Ibrahim T.Splicing factor ratio as an index of epithelial-mesenchymal transition and tumor aggressiveness in breast cancer..Oncotarget2017;8:2423-36 PMCID:PMC5356812

[25] Vanharanta S,Shu W,Zou Y.Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer..Elife2014;3:1-24 PMCID:PMC4073284

[26] Lee NS,Souaiaia T,Herstein J.Non-coding RNAs derived from an alternatively spliced REST transcript (REST-003) regulate breast cancer invasiveness..Sci Rep2015;5:11207 PMCID:PMC4459148

[27] Brown DM.Metadherin, a cell surface protein in breast tumors that mediates lung metastasis..Cancer Cell2004;5:365-74

[28] Hu G,Yang Q,Blanco MA.MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer..Cancer Cell2009;15:9-20 PMCID:PMC2676231

[29] Meng X,Yang S,Xiong Z.Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein..J Biol Chem2012;287:4485-91 PMCID:PMC3281628

[30] Blanco MA,Hua Y,Wei Y.Identification of staphylococcal nuclease domain-containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions..J Biol Chem2011;286:19982-92 PMCID:PMC3103372

[31] Yoo BK,Gredler R,Emdad L.Increased RNA-induced Silencing complex (RISC) activity contributes to hepatocellular carcinoma..Hepatology2011;53:1538-48 PMCID:PMC3081619

[32] Meng X,Leslie KK.Drug resistance mediated by AEG-1/MTDH/LYRIC..Adv Cancer Res2013;120:135-57 PMCID:PMC3967868

[33] Wan L,Yuan S,Guo F.MTDH-SND1 interaction is crucial for expansion and activity of tumor-initiating cells in diverse oncogene- and carcinogen-induced mammary tumors..Cancer Cell2014;26:92-105 PMCID:PMC4101059

[34] Cappellari M,Paronetto MP,Fimia GM.The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells..Oncogene2014;33:3794-802

[35] Gao X,Zhu Y,Shao J.Tudor staphylococcal nuclease (Tudor-SN) participates in small ribonucleoprotein (snRNP) assembly via interacting with symmetrically dimethylated Sm proteins..J Biol Chem2012;287:18130-41 PMCID:PMC3365748

[36] Yang J,Hong J,Yao Z.Transcriptional co-activator protein p100 interacts with snRNP proteins and facilitates the assembly of the spliceosome..Nucleic Acids Res2007;35:4485-94 PMCID:PMC1935017

[37] Chi SW,Mele A.Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps..Nature2009;460:479-86 PMCID:PMC2733940

[38] Hafner M,Burger L,Hausser J.Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP..Cell2010;141:129-41 PMCID:PMC2861495

[39] Hsu JC,Hoffman AM,Nicchitta CV.Oncoprotein AEG-1 is an endo- plasmic reticulum RNA-binding protein whose interactome is enriched in organelle resident protein-encoding mRNAs..RNA2018;24:688-703 PMCID:PMC5900566