The Role of MicroRNAs Regulated Breast Cancer Stem Cells in the Pathogenesis, Prognosis and Aggressiveness of Breast Cancer
Rasheed Agboola *
Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, South Georgia, GA, USA.
Adedeji Okikiade
Clinical Sciences, California Northstate University, Sacramento, CA, USA.
Olayinka Afolayan-Oloye
Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA.
*Author to whom correspondence should be addressed.
Abstract
Breast cancer is a leading cause of cancer related death among women worldwide and it is a complex disease characterized by its heterogeneity. The heterogenous characteristic of the breast cancer is responsible for its aggressiveness and treatment resistance. Breast cancer stem cells (BCSCs) are population of heterogenous cells with increased propensity for proliferation, differentiation, migration, invasion and mammosphere formation with increased resistance to treatment. They have ability to initiate and propagate cancer cells population and share similarity with the normal stem cells in relation to their expressions of cell surface markers; Cluster of Differentiation 44 positive (CD44+), Cluster of Differentiation 24 negative/low (CD24-/low) and Alkaline dehydrogenase 1 (ALDH1).
MicroRNAs (miRNAs) are responsible for the RNA silencing and post-transcriptional regulation of the gene expression. MicroRNAs (miRNAs) control gene expression by acting as oncogenes or tumor suppressor genes. The epigenetic mechanisms are used for the regulation of miRNAs expression in the breast cancer, and this can be targeted to reverse the cancer progression. This review aims to provide an overview of the pathogenic mechanism of the microRNA’s expressions on the breast cancer stem cells in controlling the prognosis and aggressiveness of breast cancer disease. This is done by highlighting the regulatory mechanism of miRNA expressions on the BCSCs.
Dysregulation of the MicroRNAs expression in the breast cancer stem cells and upregulated miRNAs expression were identified in the breast cancer stem cells (BCSCs), including miR-10b, miR-21, miR-155, miR-181, miR-183, miR-210 and miR-221/222, and the downregulated miRNAs expression in BCSCs include Let-7, miR-22, miR-30e, miR-31, miR-103/107, miR-200, miR-205, miR-335, miR-449a, miR-519c, miR-600, miR-708, miR-760. Studies showed association between the miRNA expression and breast cancer metastasis and aggressiveness. MicroRNAs were noticed to have a regulatory effect on neovascularization, drug resistance, and cancer metastasis. They can be used as predictive indicators in determining prognosis of breast cancer following cancer treatment and miRNAs expression can be used to determine the metastatic BCSCs for an efficient targeting mechanism and identification of the metastatic cancer cells. The systematic literature review aims at providing insight into the potential roles of microRNA in oncology especially breast cancers. The data for this study review were obtained from the Medline on OvidSP, includes PubMed of the US National Library of Medicine and the search was done through the University of Bristol Library services. This is to provide an overview of the pathogenic mechanism of microRNAs regulatory effect on the breast cancer stem cells in controlling the prognosis and aggressiveness of breast cancer disease. The review will be providing highlight of the dysregulation of oncogenic and tumor suppressor microRNAs in the breast cancer stem cells and highlighting the roles of miRNAs regulated BCSCs in the pathogenesis, prognosis, and aggressiveness of the breast cancer. We further discuss the biogenesis of miRNAs, regulatory roles of miRNAs on BCSCs, and then summarize the mechanism of miRNAs regulated BCSCs.
Keywords: MicroRNAs, breast cancer stem cells, epigenetic mechanism, dysregulation, breast cancer aggressiveness, cell surface markers
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References
Duru N, Fan M, Candas D, Menaa C, Liu HC, Nantajit D, et al. HER2‐associated radioresistance of breast cancer stem cells isolated from HER2‐negative breast cancer cells. Clin Cancer Res. 2012;18(24): 6634-47. DOI: 10.1158/1078-0432.CCR-12-1436, PMID 23091114.
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA‐200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592-603. DOI: 10.1016/j.cell.2009.07.011, PMID 19665978.
Luwor RB, Baradaran B, Taylor LE, Iaria J, Nheu TV, Amiry N, et al. Targeting Stat3 and Smad7 to restore TGF‐β cytostatic regulation of tumor cells In vitro and In vivo. Oncogene. 2013;32(19):2433-41. DOI: 10.1038/onc.2012.260, PMID 22751114.
Lee RC et al. The C. elegans heterochromic gene in Lin-4 encodes small RNAs with antiserum complementary to Lin-14. Cel. 1993;75(5):843-54. DOI: 10.1016/0092-8674
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006; 66(19):9339-44. DOI: 10.1158/0008-5472.CAN-06-3126, PMID 16990346.
Siahmansouri H, Somi MH, Babaloo Z, Baradaran B, Jadidi-Niaragh F, Atyabi F, et al. Effects of HMGA2 siRNA and doxorubicin dual delivery by chitosan nanoparticles on cytotoxicity and gene expression of HT‐29 colorectal cancer cell line. J Pharm Pharmacol. 2016;68(9): 1119-30. DOI: 10.1111/jphp.12593, PMID 27350211.
Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal T, et al. Axl is an essential epithelial‐to‐mesenchymal transition‐induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010; 107(3):1124-9. DOI: 10.1073/pnas.0909333107, PMID 20080645.
Al‐Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-7. DOI: 10.1016/j.gde.2003.11.007, PMID 15108804.
Kong LM, Liao CG, Zhang Y, Xu J, Li Y, Huang W, et al. A regulatory loop involving miR‐22, Sp1, and c‐Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res. 2014;74(14): 3764-78. DOI: 10.1158/0008-5472.CAN-13-3555, PMID 24906624.
Hartwig FP, Nedel F, Collares T, Tarquinio SB, Nör JE, Demarco FF. Oncogenic somatic events in tissue‐specific stem cells: A role in cancer recurrence? Ageing Res Rev. 2014;13:100-6. DOI: 10.1016/j.arr.2013.12.004, PMID 24374269.
Wang RA, Li ZS, Zhang HZ, Zheng PJ, Li Q, Shi J, et al. Invasive cancers are not necessarily from preformed in situ tumors—an alternative way of carcinogenesis from misplaced stem cells. J Cell Mol Med. 2013;17(7):921-6. DOI: 10.1111/jcmm.12078
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. Let −7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell. 2007;131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054, PMID 18083101.
Tang J, Ahmad A, Sarkar FH. The role of microRNAs in breast cancer migration, invasion and metastasis. Int J Mol Sci. 2012;13(10):13414-37. DOI: 10.3390/ijms131013414, PMID 23202960.
Takahashi RU, Miyazaki H, Ochiya T. The role of microRNAs in the regulation of cancer stem cells. Front Genet. 2014; 4:295. DOI: 10.3389/fgene.2013.00295, PMID 24427168.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR‐200 family and miR‐205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593-601. DOI: 10.1038/ncb1722, PMID 18376396.
Ryu S, McDonnell K, Choi H, Gao D, Hahn M, Joshi N, et al. Suppression of miRNA‐708 by polycomb group promotes metastases by calcium‐induced cell migration. Cancer Cell. 2013;23(1):63-76. DOI: 10.1016/j.ccr.2012.11.019, PMID 23328481.
Pandey DP, Picard D. MiR‐22 inhibits estrogen signaling by directly targeting the estrogen receptor α mRNA. Mol Cell Biol. 2009;29(13):3783-90. DOI: 10.1128/MCB.01875-08, PMID 19414598.
Kong LM, Liao CG, Zhang Y, Xu J, Li Y, Huang W, et al. A regulatory loop involving miR‐22, Sp1, and c‐Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res. 2014;74(14): 3764-78. DOI: 10.1158/0008-5472.CAN-13-3555, PMID 24906624.
Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. 4 (PDCD4) is an important functional target of the microRNA miR‐21 in breast cancer cells. J Biol Chem. 2008;283(2): 1026-33. DOI: 10.1074/jbc.M707224200, PMID 17991735.
Trivellin G, Butz H, Delhove J, Igreja S, Chahal HS, Zivkovic V, et al. MicroRNA miR‐107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor‐interacting protein in vitro. Am J Physiol Endocrinol Metab. 2012;303(6):E708-19. DOI: 10.1152/ajpendo.00546.2011, PMID 22811466.
Moncini S, Salvi A, Zuccotti P, Viero G, Quattrone A, Barlati S, et al. The role of miR‐103 and miR‐107 in regulation of CDK5R1 expression and in cellular migration. PLOS ONE. 2011;6(5):e20038. DOI: 10.1371/journal.pone.0020038, PMID 21625387.
Iorio MV, Casalini P, Piovan C, Di Leva G, Merlo A, Triulzi T, et al. microRNA‐205 regulates HER3 in human breast cancer. Cancer Res. 2009;69(6):2195-200. DOI: 10.1158/0008-5472.CAN-08-2920, PMID 19276373.
Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008;451(7175):147-52. DOI: 10.1038/nature06487, PMID 18185580.
Png KJ, Yoshida M, Zhang XH, Shu W, Lee H, Rimner A, et al. MicroRNA‐335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes Dev. 2011;25(3):226-31. DOI: 10.1101/gad.1974211, PMID 21289068.
Valastyan S, Chang A, Benaich N, Reinhardt F, Weinberg RA. Concurrent suppression of integrin α5, radixin, and RhoA phenocopies the effects of miR‐31 on metastasis. Cancer Res. 2010;70(12):5147-54. DOI: 10.1158/0008-5472.CAN-10-0410, PMID 20530680.
Cha ST, Chen PS, Johansson G, Chu CY, Wang MY, Jeng YM, et al. MicroRNA‐519c suppresses hypoxia‐inducible factor‐1α expression and tumor angiogenesis. Cancer Res. 2010;70(7):2675-85. DOI: 10.1158/0008-5472.CAN-09-2448, PMID 20233879.
Xu B, Zhang X, Wang S, Shi B. MiR‐449a suppresses cell migration and invasion by targeting PLAGL2 in breast cancer. Pathol Res Pract. 2018;214(5):790-5. DOI: 10.1016/j.prp.2017.12.012, PMID 29653747.
El Helou R, Pinna G, Cabaud O, Wicinski J, Bhajun R, Guyon L, et al. miR‐600 acts as a bimodal switch that regulates breast cancer stem cell fate through WNT signaling. Cell Rep. 2017;18(9):2256-68. DOI: 10.1016/j.celrep.2017.02.016, PMID 28249169.
Han ML, Wang F, Gu YT, Pei XH, Ge X, Guo GC et al. ‐t, Pei.‐h, et. MicroR‐760 suppresses cancer stem cell subpopulation and breast cancer cell proliferation and metastasis: by down‐regulating NANOG. Biomed Pharmacother. 2016;80:304-10. DOI: 10.1016/j.biopha.2016.03.024, PMID 27133070.
Schwarzenbacher D, Balic M, Pichler M. The role of microRNAs in breast cancer stem cells. Int J Mol Sci. 2013; 14(7):14712-23. DOI: 10.3390/ijms140714712, PMID 23860207.
Liu L, Zhou W, Cheng CT, Ren X, Somlo G, Fong MY, et al. TGFβ induces ”BRCAness” and sensitivity to PARP inhibition in breast cancer by regulating DNA‐repair genes. Mol Cancer Res. 2014;12(11):1597-609. DOI: 10.1158/1541-7786.MCR-14-0201, PMID 25103497.
Lowery AJ, Miller N, Dwyer RM, Kerin MJ. Dysregulated miR‐183 inhibits migration in breast cancer cells. BMC Cancer. 2010;10(1):502. DOI: 10.1186/1471-2407-10-502, PMID 20858276.
Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa‐miR‐210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14(5): 1340-8. DOI: 10.1158/1078-0432.CCR-07-1755, PMID 18316553.
Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E. MicroRNA‐10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer. 2009; 125(6):1407-13. DOI: 10.1002/ijc.24522, PMID 19536818.
Yang J, Mani SA, Weinberg RA. Exploring a new twist on tumor metastasis. Cancer Res. 2006;66(9):4549-52. DOI: 10.1158/0008-5472.CAN-05-3850, PMID 16651402.
Ma L. Role of miR‐10b in breast cancer metastasis. Breast Cancer Res. 2010; 12(5):210. DOI: 10.1186/bcr2720, PMID 21067538.
Yan LX, Huang XF, Shao Q, Huang MY, Deng L, Wu QL, et al. MicroRNA miR‐21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA. 2008;14(11):2348-60. DOI: 10.1261/rna.1034808, PMID 18812439.
Selcuklu SD, Donoghue MT, Spillane C. miR‐21 as a key regulator of oncogenic processes. Biochem Soc Trans. 2009; 37(4):918-25. DOI: 10.1042/BST0370918, PMID 19614619.
Huang Q, Gumireddy K, Schrier M, Le Sage C, Nagel R, Nair S, et al. The microRNAs miR‐373 and miR‐520c promote tumor invasion and metastasis. Nat Cell Biol. 2008;10(2):202-10. DOI: 10.1038/ncb1681, PMID 18193036.
Lambertini E, Lolli A, Vezzali F, Penolazzi L, Gambari R, Piva R. Correlation between Slug transcription factor and miR‐221 in MDA‐MB‐231 breast cancer cells. BMC Cancer. 2012;12(1):445. DOI: 10.1186/1471-2407-12-445, PMID 23031797.
Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O’Brien C, et al. miR‐221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial‐to‐mesenchymal transition in breast cancer. Sci Signal. 2011;4(186):pt5. DOI: 10.1126/scisignal.2002258, PMID 21868360, pt5-pt5.
Li B, Lu Y, Yu L, Han X, Wang H, Mao J, et al. miR‐221/222 promote cancer stem‐like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF‐κB/COX‐2 activation. Chem Biol Interact. 2017;277:33-42. DOI: 10.1016/j.cbi.2017.08.014, PMID 28844858.
Hemmatzadeh M, Mohammadi H, Jadidi‐Niaragh F, Asghari F, Yousefi M. The role of oncomirs in the pathogenesis and treatment of breast cancer. Biomed Pharmacother. 2016;78:129-39. DOI: 10.1016/j.biopha.2016.01.026, PMID 26898434.
Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, Ralfkiaer E, et al. Onco‐miR‐155 targets SHIP1 to promote TNFα‐dependent growth of B cell lymphomas. EMBO Mol Med. 2009;1(5):288-95. DOI: 10.1002/emmm.200900028, PMID 19890474.
Asadzadeh Z, Mohammadi H, Safarzadeh E, Hemmatzadeh M, Mahdian-Shakib A, Jadidi-Niaragh F, et al. The paradox of Th17 cell functions in tumor immunity. Cell Immunol. 2017;322:15-25. DOI: 10.1016/j.cellimm.2017.10.015, PMID 29103586.
Robertson NM, Yigit MV. The role of microRNA in resistance to breast cancer therapy. Wiley Interdiscip Rev RNA. 2014;5(6):823-33. DOI: 10.1002/wrna.1248, PMID 25044299.
Pileczki V, Cojocneanu‐Petric R, Maralani M, Neagoe IB, Sandulescu R. MicroRNAs as regulators of apoptosis mechanisms in cancer. Clujul Med. 2016;89(1):50-5. DOI: 10.15386/cjmed-512, PMID 27004025.
Bouchie A. First microRNA mimic enters clinic. Nature research. 2013;31:577-.
Eto K, Iwatsuki M, Watanabe M, Ida S, Ishimoto T, Iwagami S, et al. The microRNA‐21/PTEN pathway regulates the sensitivity of HER2‐positive gastric cancer cells to trastuzumab. Ann Surg Oncol. 2014;21(1):343-50. DOI: 10.1245/s10434-013-3325-7, PMID 24154840.
Sotiriou C et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA. 2003;101:2999-3004.
Kumar R et al. MicroRNA Regulates estrogen receptor alpha in Breast Cancer metastasis. J Cancer Res Ther Oncol. 2014.
Howard EW, Yang X. MicroRNA regulation in estrogen receptor positive breast cancer and endocrine theory. Biol Proced Online. 2018;20(1):17. DOI: 10.1186/s12575-018-0082-9
Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, et al. MicroRNA‐221/222 negatively regulates estrogen receptorα and is associated with tamoxifen resistance in breast cancer. J Biol Chem. 2008;283(45):31079-86.
DOI: 10.1074/jbc.M806041200, PMID 18790736.
Xue J, Chi Y, Chen Y, Huang S, Ye X, Niu J, et al. miRNA‐621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity. Oncogene. 2016;35(4):448-58. DOI: 10.1038/onc.2015.96, PMID 25867061.
Rucci N, Teti A. Osteomimicry: How tumor cells try to deceive the bone. Front Biosci (Schol Ed). 2010;2(3):907-15. DOI: 10.2741/s110, PMID 20515833.
Lin X, Chen W, Wei F, Zhou BP, Hung MC, Xie X. Nanoparticle delivery of miR‐34a eradicates long‐term‐cultured breast cancer stem cells via targeting C22ORF28 directly. Theranostics. 2017;7(19):4805-24. DOI: 10.7150/thno.20771, PMID 29187905.
Loh HY, Norman BP, Lai KS, Rahman NMANA, Alitheen NBM, Osman MA. The regulatory role of microRNAs in Breast Cancer. Int J Mol Sci. 2019;20(19):4940. DOI: 10.3390/ijms20194940, PMID 31590453.
Martinez-Gutierrez AD, Cantú de León D, Millan-Catalan O, Coronel-Hernandez J, Campos-Parra AD, Porras-Reyes F, et al. Identification of miRNA master regulator in breast cancer. Cells. 2020;9(7):1610. DOI: 10.3390/cells9071610, PMID 32635183.
Niu T, Zhang W, Xiao W. MicroRNA regulation of cancer stem cells in the pathogenesis of breast cancer. Cancer Cell Int. 2021;21(1):Article number:31. DOI: 10.1186/s12935-020-01716-8, PMID 33413418.
Das PK, Siddika MA, Asha SY, Aktar S, Rakib MA, Khanam JA, et al. MicroRNAs, a promising target for breast cancer stem cells. Mol Diagn Ther. 2020;24(1):69-83. DOI: 10.1007/s40291-019-00439-5, PMID 31758333.
Flores-Huerta N, Silva-Cázares MB, Arriaga-Pizano LA, Prieto-Chávez JL, López-Camarillo C. LncRNAs and microRNAs as essential regulators of stemness in breast cancer stem cells. Biomolecules. 2021;11(3):380. DOI: 10.3390/biom11030380, PMID 33802575.
Yang Z, Liu Z. The emerging role of microRNAs in breast cancer. Volume 2020/Article. J Oncol. Doi.org/10/1155/2020/916095. 2020;2020:ID9160905. DOI: 10.1155/2020/9160905, PMID 32714393.
Saghar Y, et al. Mechanistic pathways of malignancy in breast cancer stem cells. Front. Oncol, sec. Mol Cell Oncol. 2020;10-2020. DOI: 10.3389/fonc.2020.00452
El-Osaily HH, Ibrahim IH, Essawi ML, Salem SM. Impact of miRNAs expression modulation on the methylation status of breast cancer stem cell related genes. Clin Transl Oncol. 2021;23(7):1440-51. DOI: 10.1007/s12094-020-02542-0, PMID 33433838.
Duong T, et al. Diagnostic and prognostic value of miR-200 family in breast cancer: A meta-analysis and systematic review. Cancer Epidemiol. 2022;77:102097. DOI: 10.1016/j.canep.2022102097
Ma Y, Shen N, Wicha MS, Luo M. The roles of the Let-7 family of microRNAs in the regulation of cancer stemness. Cells. 2021;10(9):2415. DOI: 10.3390/cells10092415, PMID 34572067.
Richard V, Davey MG, Annuk H, Miller N, Dwyer RM, Lowery A, et al. MicroRNAs in molecular classification and pathogenesis of breast tumors. Cancers. 2021;13(21):5332. DOI: 10.3390/cancers13215332, PMID 34771496.
Zhang R, Tu J, Liu S. Novel molecular regulators of breast cancer stem cell plasticity and heterogeneity. Semin Cancer Biol. 2022;82:11-25. DOI: 10.1016/j.semcancer.2021.03.008, PMID 33737107.