Potential targeted therapy: The role of MicroRNAs in breast cancer metastasis via epithelial-mesenchymal transition and cancer stem cell regulation
Abstract
Abstract
In the advancement of breast cancer treatment, metastatic breast cancer is remaining as an incurable disease. It contributes to almost 90% of cancer-related death in breast cancer cases. Epithelial to Mesenchymal Transition (EMT) is a serial change of the epithelial cell to gain the mesenchymal-like phenotype. In cancer, the cells that undergo the EMT lose the adherent junction protein, cell polarity, and gain the invasive phenotype. Recent studies showed that the EMT induces the cancer stem cell-like phenotypes in cancer cells. These cells possess self-renewal ability, and multi-lineage differentiation capacity to generate the new bulk of tumor during cancer distant metastasis. Both EMT and cancer stem cells take responsibility in drug-resistant, and relapse cases in breast cancer. In the last decades, a new type of non-coding RNA, microRNA (miR) shows have an important role in the normal physiological and pathophysiological condition such as cancer. Recent studies revealed that the EMT is regulated by microRNAs. In this review, we discussed the microRNAs regulation on the EMT process through TGF-β, and Wnt signaling pathways in breast cancer. Understanding of microRNA regulation in EMT in breast cancer metastasis gives a chance to explore a new therapy approach to improve the prognosis of breast cancer patients. In addition, we also explored several potential approaches targeting microRNA as a new approach of cancer treatment.
Keywords: breast cancer, microRNA, EMT, metastasis, targeted therapy.
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359–86.
http://doi.org/10.1002/ijc.29210
Lord SJ, Kiely BE, Pearson S-A, Daniels B, O’Connell DL, Beith J, et al. Metastatic breast cancer incidence, site and survival in Australia, 2001–2016: a population-based health record linkage study protocol. BMJ Open 2019; 9:e026414.
https://doi.org/10.1136/bmjopen-2018-026414
Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer 2019; 19:1091.
https://doi.org/10.1186/s12885-019-6311-z
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29:4741–51.
http://doi.org/10.1038/onc.2010.215.
Owens TW, Naylor MJ. Breast cancer stem cells. Front Physiol 2013; 4:225.
https://doi.org./10.3389/fphys.2013.00225
Scioli MG, Storti G, D’Amico F, Gentile P, Fabbri G, Cervelli V, et al. The role of breast cancer stem cells as a prognostic marker and a target to improve the efficacy of breast cancer therapy. Cancers (Basel) 2019; 11:1021.
https://doi.org/10.3390/cancers11071021
Konge J, Leteurtre F, Goislard M, Biard D, Morel-Altmeyer S, Vaurijoux A, et al. Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant. Oncotarget 2018; 9:23519–31.
https://doi.org/10.18632/oncotarget.25240
Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 2009; 11(4):R46.
https://doi.org/10.1186/bcr2333
Zhang J, Tian X, Xing J. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J Clin Med 2016; 5:41.
https://doi.org/ 10.3390/jcm5040041
Choi J, Sun YP, Joo CK. Transforming growth factor-β1 represses E-cadherin production via Slug expression in lens epithelial cells. Investig Ophthalmol Vis Sci 2007; 48:2708–18.
https://org.doi/10.1167/iovs.06-0639
Bartel DP. MicroRNAs : genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-97.
https://doi.org/10.1016/S0092-8674(04)00045-5
Tiwari N, Gheldof A, Tatari M, Christofori G. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 2012; 22:194-207.
https://doi.orf/10.1016/j.semcancer.2012.02.013
Katz E, Dubois-Marshall S, Sims AH, Gautier P, Caldwell H, Meehan RR, et al.An in vitro model that recapitulates the epithelial to mesenchymal transition (EMT) in human breast cancer. PLoS One 2011; 6:e17083.
https://doi.org/10.1371/journal.pone.0017083
Shuang ZY, Wu WC, Xu J, Lin G, Liu YC, Lao XM, et al. Transforming growth factor-β1-induced epithelial-mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma. Cancer Lett 2014; 354:320-8.
https://doi.org/10.1016/j.canlet.2014.08.030
Huang J, Li H, Ren G. Epithelial-mesenchymal transition and drug resistance in breast cancer. Int J Oncol 2015; 47:840-8.
https://doi.org/10.3892/ijo.2015.3084
Johansson J, Berg T, Kurzejamska E, Pang M, Tabor V, Jansson M, et al. MiR-155-mediated loss of C/EBP b shifts the TGF- b response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer. Oncogene 2013; 32:5614-24.
https://doi.org/10.1038/onc.2013.322
Li X, Xu Y, Chen Y, Chen S, Jia X, Sun T, et al. SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/β-catenin signal network. Cancer Lett 2013; 336:379–89.
Shan S, Lv Q, Zhao Y, Liu C, Sun Y, Xi K, et al. Wnt/β-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells. Int J Clin Exp Pathol 2015; 8:12357-67.
Jang G-B, Kim J-Y, Cho S-D, Park K-S, Jung J-Y, Lee H-Y, et al. Blockade of Wnt/β-catenin signaling suppresses breast cancer metastasis by inhibiting CSC-like phenotype. Sci Rep 2015; 5:12465.
https://doi.org/10.1038/srep12465
Yang J, Hou Y, Zhou M, Wen S, Zhou J, Xu L, et al. Twist induces epithelial-mesenchymal transition and cell motility in breast cancer via ITGB1-FAK/ILK signaling axis and its associated downstream network. Int J Biochem Cell Biol 2016; 71:62-71.
https://doi.org/10.1016/j.biocel.2015.12.004
Glackin CA. Targeting the Twist and Wnt signaling pathways in metastatic breast cancer. Maturitas 2014; 79(1):48-51.
https://doi.org/10.1016/j.maturitas.2014.06.015
MacFarlane L-A, Murphy PR. MicroRNA: biogenesis, function and role in cancer. Curr Genomics 2010; 11:537–61.
https://doi.org/10.2174/138920210793175895
Nishihara T, Zekri L, Braun JE, Izaurralde E. MiRISC recruits decapping factors to miRNA targets to enhance their degradation. Nucleic Acids Res 2013; 41:8692–705.
https://doi.org/10.1093/nar/gkt619
Liu T, Hu K, Zhao Z, Chen G, Ou X, Zhang H, et al. MicroRNA-1 down-regulates proliferation and migration of breast cancer stem cells by inhibiting the Wnt/β-catenin pathway. Oncotarget 2015; 6:41638–49.
https://doi.org/10.18632/oncotarget.5873
Peng J, Yuan C, Wu Z, Wang Y, Yin W, Lin Y, et al. Upregulation of microRNA‑1 inhibits proliferation and metastasis of breast cancer. Mol Med Rep 2020; 22:454–64.
https://doi.org/10.3892/mmr.2020.11111
Zhao S, Han J, Zheng L, Yang Z, Zhao L, Lv Y. MicroRNA-203 regulates growth and metastasis of breast cancer. Cell Physiol Biochem 2015; 37(1):35–42.
https://doi.org/10.1159/000430331
Mikami S, Katsube KI, Oya M, Ishida M, Kosaka T, Mizuno R, et al. Expression of snail and slug in renal cell carcinoma: E-cadherin repressor snail is associated with cancer invasion and prognosis. Lab Investig 2011; 91(10):1443–58.
https://doi.org/10.1038/labinvest.2011.111
Zhao H, Yang Z, Wang X, Zhang X, Wang M, Wang Y, et al. Triptolide inhibits ovarian cancer cell invasion by repression of matrix metalloproteinase 7 and 19 and upregulation of E-cadherin. Exp Mol Med 2012; 44:633-41.
Taube JH, Malouf GG, Lu E, Sphyris N, Vijay V, Ramachandran PP, et al. Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Sci Rep 2013; 3:2687.
https://doi.org/10.1038/srep02687
Su CM, Lee WH, Wu ATH, Lin YK, Wang LS, Wu CH, et al. Pterostilbene inhibits triple-negative breast cancer metastasis via inducing microRNA-205 expression and negatively modulates epithelial-to-mesenchymal transition. J Nutr Biochem 2015; 26:675–85.
https://doi.org/10.1016/j.jnutbio.2015.01.005
Xiao, Humphries, Yang, Wang. MiR-205 Dysregulations in Breast Cancer: The Complexity and Opportunities. Noncoding RNA2019; 5(4):53.
https://doi.org/10.3390/ncrna5040053
Liu Y, Zhao J, Zhang P-Y, Zhang Y, Sun S-Y, Yu S-Y, et al. MicroRNA-10b targets E-cadherin and modulates breast cancer metastasis. Med Sci Monit 2012; 18:BR299-308.
https://doi.org/10.12659/msm.883262
Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449(7163):682–8.
https://doi.org/10.1038/nature06174
Rostas JW III, Pruitt HC, Metge BJ, Mitra A, Bailey SK, Bae S, et al. microRNA-29 negatively regulates EMT regulator N-myc interactor in breast cancer. Mol Cancer 2014; 13:200.
https://doi.org/10.1186/1476-4598-13-200
Devine DJ, Rostas JW, Metge BJ, Das S, Mulekar MS, Tucker JA, et al. Loss of N-Myc interactor promotes epithelial-mesenchymal transition by activation of TGF-β/SMAD signaling. Oncogene 2014; 33(20):2620–8.
https://doi.org/10.1038/onc.2013.215
Wu Y, Shi W, Tang T, Wang Y, Yin X, Chen Y, et al. miR-29a contributes to breast cancer cells epithelial–mesenchymal transition, migration, and invasion via down-regulating histone H4K20 trimethylation through directly targeting SUV420H2. Cell Death Dis 2019; 10:176.
https://doi.org/10.1038/s41419-019-1437-0
Zhang J, Liu D, Feng Z, Mao J, Zhang C, Lu Y, et al. MicroRNA-138 modulates metastasis and EMT in breast cancer cells by targeting vimentin. Biomed Pharmacother 2016; 77:135–41.
https://doi.org/10.1016/j.biopha.2015.12.018
Zhao C, Ling X, Li X, Hou X, Zhao D. MicroRNA-138-5p inhibits cell migration, invasion and EMT in breast cancer by directly targeting RHBDD1. Breast Cancer 2019; 26(6):817–25.
https://doi.org/10.1007/s12282-019-00989-w
Ward A, Balwierz A, Zhang JD, Küblbeck M, Pawitan Y, Hielscher T, et al. Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. Oncogene 2013; 32:1173–82.
https://doi.org/10.1038/onc.2012.128
Li X, Kong X, Huo Q, Guo H, Yan S, Yuan C, et al. Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition. Cancer Sci 2011; 102(6):1151–7.
https://doi.org/10.1111/j.1349-7006.2011.01919.x
Yu DD, Lv MM, Chen WX, Zhong SL, Zhang XH, Chen L, et al. Role of miR-155 in drug resistance of breast cancer. Tumor Biol 2015; 36(3):1395–401.
https://doi.org/10.1007/s13277-015-3263-z
Almeida MI, Reis RM, Calin GA. MYC-microRNA-9-metastasis connection in breast cancer. Cell Res 2010; 20:603–4.
https://doi.org/10.1038/cr.2010.70
Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene 2007; 26:2799–803.
https://doi.org/10.1038/sj.onc.1210083
Gibson NW. Clinical engineered microRNA therapeutics. JR Coll Physician Edinb 2014; 44(3):196–200.
https://doi.org/ 10.4997/JRCPF.2014.302
Lennox KA, Owczarzy R, Thomas DM, Walder JA, Behlke MA. Improved performance of anti-miRNA oligonucleotides using a novel non-nucleotide modifier. Mol Ther Nucleic Acids 2013; 2:e117.
https://doi.org/10.1038/mtna.2013.46
Shu D, Li H, Shu Y, Xiong G, Carson WE, Haque F, et al.Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS Nano2015; 9:9731–40.
