Unveiling Role of MicroRNAs in Metastasizing Triple Negative Breast
Cancer: From Therapeutics to Delivery

Acharya      Balkrishna; Rashmi      Mittal; Vedpriya      Arya

doi:10.2174/1389450124666230308154551

Abstract

Triple negative breast cancers are malignant, heterogeneous tumors with high histological grades, increased reoccurrence, and cancer-related death rates. TNBC metastasis to the brain, lungs, liver, and lymph nodes is a complex process regulated by epithelial to mesenchymal transition, intravasation, extravasation, stem cell niche, and migration. Aberrant expression of miRNAs, also known as a transcriptional regulators of genes, may function as oncogenes or tumor suppressors. In this review, we systematically elucidated the biogenesis and tumor suppressor role of miRNA in targeting distant metastasis of TNBC cells and the above-mentioned underlying mechanisms involved in complicating the disease. Apart from their therapeutic implications, the emerging roles of miRNAs as prognostic markers have also been discussed. To overcome delivery bottlenecks, RNA nanoparticles, nano-diamonds, exosomes, and mesoporous silica nanoparticle-mediated delivery of miRNAs have been contemplated. Altogether, the present review article uncovers the potential role of miRNA in antagonizing distant metastasis of TNBC cells, and highlights their clinical significance as prognostic markers and possible drug delivery strategies to enhance the likely outcome of miRNA-based therapy against the disease.

Keywords: miRNAs, metastasis, prognosis, therapeutics, delivery, stem cells.

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[1]
Hong HC, Chuang CH, Huang WC, et al. A panel of eight microRNAs is a good predictive parameter for triple-negative breast cancer relapse. Theranostics  2020; 10(19): 8771-89.
 [http://dx.doi.org/10.7150/thno.46142] [PMID: 32754277]

[2]
Thomsen KG, Terp MG, Lund RR, et al. miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations. Oncotarget  2015; 6(30): 29224-39.
 [http://dx.doi.org/10.18632/oncotarget.4942] [PMID: 26317550]

[3]
Li Y, Deng X, Zeng X, Peng X. The role of Mir-148a in cancer. J Cancer  2016; 7(10): 1233-41.
 [http://dx.doi.org/10.7150/jca.14616] [PMID: 27390598]

[4]
Delgir S, Ilkhani K, Safi A, et al. The Expression of miR-513c and miR-3163 was downregulated in tumor tissues compared with margin tissues of patients with breast cancer. BMC Med Genomics  2021; 14(1): 1-2.

[5]
Koleckova M, Janikova M, Kolar Z. MicroRNAs in triple-negative breast cancer. Neoplasma  2018; 65(1): 1-13.
 [http://dx.doi.org/10.4149/neo_2018_170115N36] [PMID: 29322783]

[6]
Wu X, Ding M, Lin J. Three-microRNA expression signature predicts survival in triple-negative breast cancer. Oncol Lett  2020; 19(1): 301-8.
 [PMID: 31897142]

[7]
Angius A, Cossu-Rocca P, Arru C, et al. Modulatory Role of microRNAs in triple negative breast cancer with basal-like phenotype. Cancers (Basel)  2020; 12(11): 3298.
 [http://dx.doi.org/10.3390/cancers12113298] [PMID: 33171872]

[8]
Mehrgou A, Akouchekian M. Therapeutic impacts of microRNAs in breast cancer by their roles in regulating processes involved in this disease. J Res Med Sci  2017; 22: 130.

[9]
Li J, Lai Y, Ma J, et al. miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer. BMC Cancer  2017; 17(1): 745.
 [http://dx.doi.org/10.1186/s12885-017-3674-x] [PMID: 29126392]

[10]
Gupta I, Rizeq B, Vranic S, Moustafa AEA, Al Farsi H. Circulating miRNAs in HER2-positive and triple negative breast cancers: Potential biomarkers and therapeutic targets. Int J Mol Sci  2020; 21(18): 6750.
 [http://dx.doi.org/10.3390/ijms21186750] [PMID: 32942528]

[11]
Abdel-Sater F, Najar M, Fayyad-Kazan H. Triple negative breast cancer: MicroRNA expression profile and novel discriminators according to BRCA1 status. J Cell Physiol  2020; 235(6): 5204-12.
 [http://dx.doi.org/10.1002/jcp.29398] [PMID: 31736084]

[12]
Mei J, Hao L, Wang H, et al. Systematic characterization of non- coding RNAs in triple-negative breast cancer. Cell Prolif  2020; 53(5): e12801.
 [http://dx.doi.org/10.1111/cpr.12801] [PMID: 32249490]

[13]
Sabit H, Cevik E, Tombuloglu H, Abdel-Ghany S, Tombuloglu G, Esteller M. Triple negative breast cancer in the era of miRNA. Crit Rev Oncol Hematol  2021; 157: 103196.
 [http://dx.doi.org/10.1016/j.critrevonc.2020.103196] [PMID: 33307198]

[14]
Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA  2004; 101(9): 2999-3004.
 [http://dx.doi.org/10.1073/pnas.0307323101] [PMID: 14973191]

[15]
Cascione L, Gasparini P, Lovat F, et al. Integrated microRNA and mRNA signatures associated with survival in triple negative breast cancer. PLoS One  2013; 8(2): e55910.
 [http://dx.doi.org/10.1371/journal.pone.0055910] [PMID: 23405235]

[16]
Chang YY, Kuo WH, Hung JH, et al. Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer  2015; 14(1): 36.
 [http://dx.doi.org/10.1186/s12943-015-0301-9] [PMID: 25888956]

[17]
Cantini L, Bertoli G, Cava C, et al. Identification of microRNA clusters cooperatively acting on epithelial to mesenchymal transition in triple negative breast cancer. Nucleic Acids Res  2019; 47(5): 2205-15.
 [http://dx.doi.org/10.1093/nar/gkz016] [PMID: 30657980]

[18]
D’Ippolito E, Iorio M. MicroRNAs and triple negative breast cancer. Int J Mol Sci  2013; 14(11): 22202-20.
 [http://dx.doi.org/10.3390/ijms141122202] [PMID: 24284394]

[19]
Umeh-Garcia M, Simion C, Ho PY, et al. A novel bioengineered miR-127 prodrug suppresses the growth and metastatic potential of triple-negative breast cancer cells. Cancer Res  2020; 80(3): 418-29.
 [http://dx.doi.org/10.1158/0008-5472.CAN-19-0656] [PMID: 31694904]

[20]
Tang Q, Ouyang H, He D, Yu C, Tang G. MicroRNA-based potential diagnostic, prognostic and therapeutic applications in triple-negative breast cancer. Artif Cells Nanomed Biotechnol  2019; 47(1): 2800-9.
 [http://dx.doi.org/10.1080/21691401.2019.1638791] [PMID: 31284781]

[21]
Kabil N. miR-484 functions as an Onco-miR in triple negative breast cancer. 2018.

[22]
Balkrishna A, Mittal R, Arya V. Unveiling role of MicroRNAs as treatment strategy and prognostic markers in triple negative breast cancer. Curr Pharm Biotechnol  2020; 21(15): 1569-75.
 [http://dx.doi.org/10.2174/1389201021666200627201535] [PMID: 32593278]

[23]
Althoff K, Lindner S, Odersky A, et al. miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin. Int J Cancer  2015; 136(6): 1308-20.
 [http://dx.doi.org/10.1002/ijc.29091] [PMID: 25046253]

[24]
Phan B, Majid S, Ursu S, et al. Tumor suppressor role of microRNA-1296 in triple-negative breast cancer. Oncotarget  2016; 7(15): 19519-30.
 [http://dx.doi.org/10.18632/oncotarget.6961] [PMID: 26799586]

[25]
Bayraktar R, Pichler M, Kanlikilicer P, et al. MicroRNA 603 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting elongation factor 2 kinase. Oncotarget  2017; 8(7): 11641-58.
 [http://dx.doi.org/10.18632/oncotarget.14264] [PMID: 28036267]

[26]
Dong L, Zhou D, Xin C, Liu B, Sun P. MicroRNA-139 suppresses the tumorigenicity of triple negative breast cancer cells by targeting SOX8. Cancer Manag Res  2020; 12: 9417-28.
 [http://dx.doi.org/10.2147/CMAR.S268378] [PMID: 33061629]

[27]
Rhodes LV, Martin EC, Segar HC, et al. Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer. Oncotarget  2015; 6(18): 16638-52.
 [http://dx.doi.org/10.18632/oncotarget.3184] [PMID: 26062653]

[28]
Wang J, Li M, Han X, et al. MiR-1976 knockdown promotes epithelial–mesenchymal transition and cancer stem cell properties inducing triple-negative breast cancer metastasis. Cell Death Dis  2020; 11(7): 500.
 [http://dx.doi.org/10.1038/s41419-020-2711-x] [PMID: 32620748]

[29]
Han M, Wang Y, Liu M, et al. MiR-21 regulates epithelial-mesenchymal transition phenotype and hypoxia-inducible factor-1α expression in third-sphere forming breast cancer stem cell-like cells. Cancer Sci  2012; 103(6): 1058-64.
 [http://dx.doi.org/10.1111/j.1349-7006.2012.02281.x] [PMID: 22435731]

[30]
Teo AYT, Xiang X, Le MTN, et al. Tiny miRNAs play a big role in the treatment of breast cancer metastasis. Cancers  2021; 13(2): 337.
 [http://dx.doi.org/10.3390/cancers13020337] [PMID: 33477629]

[31]
Keklikoglou I, Koerner C, Schmidt C, et al. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways. Oncogene  2012; 31(37): 4150-63.
 [http://dx.doi.org/10.1038/onc.2011.571] [PMID: 22158050]

[32]
Xu X, Zhang Y, Jasper J, et al. MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer. Oncotarget  2016; 7(15): 20381-94.
 [http://dx.doi.org/10.18632/oncotarget.7953] [PMID: 26967387]

[33]
Yan M, Ye L, Feng X, et al. MicroRNA-590-3p inhibits invasion and metastasis in triple-negative breast cancer by targeting Slug. Am J Cancer Res  2020; 10(3): 965-74.
 [PMID: 32266103]

[34]
Gan L, Yang H, Xiong Z, Yang Z, Wang T, Lyu G. miR-518a-3p suppresses triple-negative breast cancer invasion and migration through regulation of TMEM2. Technol Cancer Res Treat  2020; 19
 [http://dx.doi.org/10.1177/1533033820977523] [PMID: 33251982]

[35]
Mekala JR, Naushad SM, Ponnusamy L, Arivazhagan G, Sakthiprasad V, Pal-Bhadra M. Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer. Gene  2018; 641: 248-58.
 [http://dx.doi.org/10.1016/j.gene.2017.10.018] [PMID: 29038000]

[36]
Chen H, Li Z, Zhang L, et al. MicroRNA-200c inhibits the metastasis of triple-negative breast cancer by targeting ZEB2, an epithelial-mesenchymal transition regulator. Ann Clin Lab Sci  2020; 50(4): 519-27.
 [PMID: 32826250]

[37]
Qiao EQ, Yang HJ, Zhang XP. Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis. J Zhejiang Uni SCI B  2020; 21(6): 495-508.

[38]
Wang J, Song C, Tang H, et al. miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer. Breast Cancer Res  2017; 19(1): 72.
 [http://dx.doi.org/10.1186/s13058-017-0865-y] [PMID: 28629464]

[39]
Kanchan RK, Siddiqui JA, Mahapatra S, Batra SK, Nasser MW. microRNAs orchestrate pathophysiology of breast cancer brain metastasis: Advances in therapy. Mol Cancer  2020; 19(1): 29.
 [http://dx.doi.org/10.1186/s12943-020-1140-x] [PMID: 32059676]

[40]
Pan JK, Lin CH, Kuo YL, et al. MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer. Oncogene  2021; 40(9): 1737-51.
 [http://dx.doi.org/10.1038/s41388-021-01654-3] [PMID: 33536579]

[41]
Dong Y, Qiu GB. Biological functions of miR-590 and its role in carcinogenesis. Front Lab Med  2017; 1(4): 173-6.
 [http://dx.doi.org/10.1016/j.flm.2017.11.002]

[42]
Weidle UH, Dickopf S, Hintermair C, Kollmorgen G, Birzele F, Brinkmann U. The role of micro RNAs in breast cancer metastasis: preclinical validation and potential therapeutic targets. Cancer Genomics Proteomics  2018; 15(1): 17-39.
 [PMID: 29275360]

[43]
Zografos E, Zagouri F, Kalapanida D, et al. Prognostic role of microRNAs in breast cancer: A systematic review. Oncotarget  2019; 10(67): 7156-78.
 [http://dx.doi.org/10.18632/oncotarget.27327] [PMID: 31903173]

[44]
Ding L, Gu H, Xiong X, et al. MicroRNAs involved in carcinogenesis, prognosis, therapeutic resistance, and applications in human triple-negative breast cancer. Cells  2019; 8(12): 1492.
 [http://dx.doi.org/10.3390/cells8121492] [PMID: 31766744]

[45]
AbdulAziz AA, MdSalleh MS, Mohamad I, Bhavaraju VMK, Gan SH, Ankathil R. microRNA expression and recurrence risk prediction in triple negative breast cancer patients. Ann Oncol  2017; 28: ix79.
 [http://dx.doi.org/10.1093/annonc/mdx697.022]

[46]
Piasecka D, Braun M, Kordek R, Sadej R, Romanska H. MicroRNAs in regulation of triple-negative breast cancer progression. J Cancer Res Clin Oncol  2018; 144(8): 1401-11.
 [http://dx.doi.org/10.1007/s00432-018-2689-2] [PMID: 29923083]

[47]
Humphries B, Wang Z, Oom AL, et al. MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis. Carcinogenesis  2014; 35(10): 2254-63.
 [http://dx.doi.org/10.1093/carcin/bgu133] [PMID: 24925028]

[48]
Li D, Wang H, Song H, et al. The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells. Oncotarget  2017; 8(49): 85276-89.
 [http://dx.doi.org/10.18632/oncotarget.19205] [PMID: 29156719]

[49]
Jang MH, Kim HJ, Gwak JM, Chung YR, Park SY. Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer. Hum Pathol  2017; 68: 69-78.
 [http://dx.doi.org/10.1016/j.humpath.2017.08.026] [PMID: 28882698]

[50]
Yao L, Liu Y, Cao Z, et al. MicroRNA-493 is a prognostic factor in triple-negative breast cancer. Cancer Sci  2018; 109(7): 2294-301.
 [http://dx.doi.org/10.1111/cas.13644] [PMID: 29777630]

[51]
Terkelsen T, Russo F, Gromov P, et al. Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration. Breast Cancer Res  2020; 22(1): 73.
 [http://dx.doi.org/10.1186/s13058-020-01295-6] [PMID: 32605588]

[52]
Miller-Kleinhenz JM, Bozeman EN, Yang L. Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances. Wiley Interdiscip Rev Nanomed Nanobiotechnol  2015; 7(6): 797-816.
 [http://dx.doi.org/10.1002/wnan.1343] [PMID: 25966677]

[53]
Shu D, Li H, Shu Y, et al. Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS Nano  2015; 9(10): 9731-40.
 [http://dx.doi.org/10.1021/acsnano.5b02471] [PMID: 26387848]

[54]
Yin H, Xiong G, Guo S, et al. Delivery of anti-miRNA for triple-negative breast cancer therapy using RNA nanoparticles targeting stem cell marker CD133. Mol Ther  2019; 27(7): 1252-61.
 [http://dx.doi.org/10.1016/j.ymthe.2019.04.018] [PMID: 31085078]

[55]
Xia Y, Deng X, Cao M, et al. Nanodiamond-based layer-by-layer nanohybrids mediate targeted delivery of miR-34a for triple negative breast cancer therapy. RSC Advances  2018; 8(25): 13789-97.
 [http://dx.doi.org/10.1039/C8RA00907D] [PMID: 35539318]

[56]
Gong C, Tian J, Wang Z, et al. Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy. J Nanobiotechnology  2019; 17(1): 93.
 [http://dx.doi.org/10.1186/s12951-019-0526-7] [PMID: 31481080]

[57]
Ahir M, Upadhyay P, Ghosh A, et al. Delivery of dual miRNA through CD44-targeted mesoporous silica nanoparticles for enhanced and effective triple-negative breast cancer therapy. Biomater Sci  2020; 8(10): 2939-54.
 [http://dx.doi.org/10.1039/D0BM00015A] [PMID: 32319481]

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DOI https://dx.doi.org/10.2174/1389450124666230308154551	Print ISSN 1389-4501
Publisher Name Bentham Science Publisher	Online ISSN 1873-5592

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