miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development

Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis.

[1]  J. Roganović,et al.  The difference in miR-21 expression levels between invasive and non-invasive breast cancers emphasizes its role in breast cancer invasion , 2014, Medical Oncology.

[2]  Li Xie,et al.  MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression , 2010, Journal of experimental & clinical cancer research : CR.

[3]  Yang Zhang,et al.  Genetic Heterogeneity of Breast Cancer Metastasis May Be Related to miR-21 Regulation of TIMP-3 in Translation , 2013, International journal of surgical oncology.

[4]  A. Lund,et al.  MicroRNA and cancer , 2012, Molecular oncology.

[5]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[6]  Akhilesh Pandey,et al.  Identification of miR‐21 targets in breast cancer cells using a quantitative proteomic approach , 2009, Proteomics.

[7]  Xiaowei Wang,et al.  miRDB: an online resource for microRNA target prediction and functional annotations , 2014, Nucleic Acids Res..

[8]  Martha R. Stampfer,et al.  miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer , 2013, PloS one.

[9]  T. Sun,et al.  High expression of the RECK gene in breast cancer cells is related to low invasive capacity , 2006 .

[10]  D. Bartel,et al.  Predicting effective microRNA target sites in mammalian mRNAs , 2015, eLife.

[11]  M. Willingham,et al.  Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors , 2003, Oncogene.

[12]  J. E. Kim,et al.  microRNAs in breast cancer: regulatory roles governing the hallmarks of cancer , 2016, Biological reviews of the Cambridge Philosophical Society.

[13]  J. Doudna,et al.  Molecular mechanisms of RNA interference. , 2013, Annual review of biophysics.

[14]  H. Hollema,et al.  Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma , 2009, BMC Cancer.

[15]  C. Croce,et al.  MicroRNA signatures in human ovarian cancer. , 2007, Cancer research.

[16]  Erik W Thompson,et al.  Epithelial to mesenchymal transition and breast cancer , 2009, Breast Cancer Research.

[17]  U. Lehmann Aberrant DNA methylation of microRNA genes in human breast cancer – a critical appraisal , 2014, Cell and Tissue Research.

[18]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[19]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[20]  Yi Zheng,et al.  miR‐21 targets the tumor suppressor RhoB and regulates proliferation, invasion and apoptosis in colorectal cancer cells , 2011, FEBS letters.

[21]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[22]  Qi-shun Zhu,et al.  MicroRNA-21 (miR-21) Regulates Cellular Proliferation, Invasion, Migration, and Apoptosis by Targeting PTEN, RECK and Bcl-2 in Lung Squamous Carcinoma, Gejiu City, China , 2014, PloS one.

[23]  C. Klinge,et al.  Estradiol downregulates miR-21 expression and miR-21 gene targets in MCF-7 breast cancer cells. , 2009 .

[24]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Shuomin Zhu,et al.  MicroRNA-21 Targets the Tumor Suppressor Gene Tropomyosin 1 (TPM1)* , 2007, Journal of Biological Chemistry.

[26]  Qiong Shao,et al.  MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. , 2008, RNA.

[27]  K. Livak,et al.  Real-time quantification of microRNAs by stem–loop RT–PCR , 2005, Nucleic acids research.

[28]  D. Helfman,et al.  Cytoskeletal changes in cell transformation and tumorigenesis. , 2001, Current opinion in genetics & development.

[29]  Manran Liu,et al.  Antagonism of miR-21 Reverses Epithelial-Mesenchymal Transition and Cancer Stem Cell Phenotype through AKT/ERK1/2 Inactivation by Targeting PTEN , 2012, PloS one.

[30]  A. Krogh,et al.  Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[31]  Z. Ling,et al.  miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma , 2015, Laboratory Investigation.

[32]  Isabella Castiglioni,et al.  MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer , 2015, Theranostics.

[33]  J. Roganović,et al.  MICRO RNA-21 EXPRESSION LEVELS IN INVASIVE BREAST CARCINOMA WITH A NON-INVASIVE COMPONENT , 2015 .

[34]  C Eng,et al.  PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. , 2001, Human molecular genetics.

[35]  Yan Zhang,et al.  Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth , 2011, Breast Cancer Research.

[36]  George A. Calin,et al.  miRNA as Potential Biomarkers of Breast Cancer in the Lebanese Population and in Young Women: A Pilot Study , 2014, PloS one.

[37]  Brigitte Rack,et al.  Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer , 2010, Breast Cancer Research.

[38]  M. Merino,et al.  miR-21 Expression in Pregnancy-Associated Breast Cancer: A Possible Marker of Poor Prognosis , 2011, Journal of Cancer.

[39]  Xingwang Yang,et al.  Combination of miR-21 with Circulating Tumor Cells Markers Improve Diagnostic Specificity of Metastatic Breast Cancer , 2015, Cell Biochemistry and Biophysics.

[40]  K. Ghoshal,et al.  MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. , 2007, Gastroenterology.

[41]  J. Roganović,et al.  Higher miR-21 expression in invasive breast carcinomas is associated with positive estrogen and progesterone receptor status in patients from Serbia , 2014, Medical Oncology.

[42]  Zhaoxia Wang,et al.  MicroRNA-21 modulates chemosensitivity of breast cancer cells to doxorubicin by targeting PTEN. , 2011, Archives of medical research.

[43]  R Sawaya,et al.  Benign reversible encephalopathy syndrome after bevacizumab therapy for metastatic ovarian cancer , 2014, Medical Oncology.

[44]  Yuan-yuan Wang,et al.  miR-21 Down-Regulation Suppresses Cell Growth, Invasion and Induces Cell Apoptosis by Targeting FASL, TIMP3, and RECK Genes in Esophageal Carcinoma , 2013, Digestive Diseases and Sciences.

[45]  E. Olson,et al.  Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. , 2010, Cancer cell.

[46]  Manran Liu,et al.  Re-expression of miR-21 contributes to migration and invasion by inducing epithelial-mesenchymal transition consistent with cancer stem cell characteristics in MCF-7 cells , 2011, Molecular and Cellular Biochemistry.

[47]  G. Hannon,et al.  Control of translation and mRNA degradation by miRNAs and siRNAs. , 2006, Genes & development.

[48]  Peter A. Jones,et al.  Epigenetics and MicroRNAs , 2007, Pediatric Research.

[49]  Yingjian Chen,et al.  Circulating microRNA-92a and microRNA-21 as novel minimally invasive biomarkers for primary breast cancer , 2012, Journal of Cancer Research and Clinical Oncology.

[50]  M. Leary,et al.  Genetic and epigenetic aspects of breast cancer progression and therapy. , 2014, Anticancer research.

[51]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[52]  S. Rakoff-Nahoum,et al.  Why Cancer and Inflammation? , 2006, The Yale journal of biology and medicine.

[53]  A. Toland,et al.  Epigenetic alterations in the breast: Implications for breast cancer detection, prognosis and treatment. , 2009, Seminars in cancer biology.

[54]  Junjie Bao,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 , 2012, Cancer science.

[55]  Anna M. Krichevsky,et al.  miR-21: a small multi-faceted RNA , 2008, Journal of cellular and molecular medicine.

[56]  Liang Chen,et al.  Role of Deregulated microRNAs in Breast Cancer Progression Using FFPE Tissue , 2013, PloS one.

[57]  Anjali J. Koppal,et al.  Supplementary data: Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites , 2010 .

[58]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[59]  M. Kay,et al.  How do miRNAs mediate translational repression? , 2010, Silence.

[60]  B. Qian,et al.  High miR-21 expression in breast cancer associated with poor disease-free survival in early stage disease and high TGF-β1 , 2009, Breast Cancer Research and Treatment.

[61]  A. Baker,et al.  Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3 , 1999, British Journal of Cancer.

[62]  Yong Li,et al.  Chinese Anti鄄 Cancer a Ssociation , 2022 .

[63]  Cristina Rodríguez-Padilla,et al.  Serum Circulating microRNA Profiling for Identification of Potential Breast Cancer Biomarkers , 2013, Disease markers.

[64]  S. Oesterreich,et al.  Epigenetics in breast cancer: what's new? , 2011, Breast Cancer Research.

[65]  Eun Sook Lee,et al.  Prognostic Implications of MicroRNA-21 Overexpression in Invasive Ductal Carcinomas of the Breast , 2011, Journal of breast cancer.

[66]  G. Martin,et al.  Cell signaling and cancer. , 2003, Cancer cell.

[67]  Zhiming Wang,et al.  miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. , 2012, Oncology reports.

[68]  F. Slack,et al.  OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma , 2010, Nature.

[69]  Hsien-Da Huang,et al.  miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions , 2013, Nucleic Acids Res..

[70]  L. Claesson‐Welsh,et al.  A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2 , 2003, Nature Medicine.

[71]  Sota Asaga,et al.  Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. , 2011, Clinical chemistry.

[72]  Yu Huang,et al.  MicroRNA-21 promotes the cell proliferation, invasion and migration abilities in ovarian epithelial carcinomas through inhibiting the expression of PTEN protein. , 2010, International journal of molecular medicine.

[73]  Chunxiang Zhang,et al.  MicroRNA-21 in Cardiovascular Disease , 2010, Journal of cardiovascular translational research.

[74]  T. Wurdinger,et al.  MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators , 2008, Molecular and Cellular Biology.

[75]  Robert A. Weinberg,et al.  Heterogeneity of stromal fibroblasts in tumor , 2007 .

[76]  Jining Lu,et al.  Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer , 2011, Breast Cancer Research.

[77]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[78]  Guan-li Huang,et al.  Clinical significance of miR-21 expression in breast cancer: SYBR-Green I-based real-time RT-PCR study of invasive ductal carcinoma. , 2009, Oncology reports.

[79]  V. Kristensen,et al.  The epigenetics of breast cancer , 2010, Molecular oncology.

[80]  A. Snyder,et al.  RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch , 2014, Oncogene.

[81]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[82]  C. Klinge,et al.  Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells , 2009, Nucleic acids research.

[83]  N. Rajewsky microRNA target predictions in animals , 2006, Nature Genetics.

[84]  N. Rajewsky,et al.  Widespread changes in protein synthesis induced by microRNAs , 2008, Nature.

[85]  Ana Kozomara,et al.  miRBase: annotating high confidence microRNAs using deep sequencing data , 2013, Nucleic Acids Res..

[86]  John A. Besse,et al.  Targeted Ablation of miR-21 Decreases Murine Eosinophil Progenitor Cell Growth , 2013, PloS one.

[87]  Michael T. McManus,et al.  Up-regulation of miR-21 by HER2/neu Signaling Promotes Cell Invasion* , 2009, The Journal of Biological Chemistry.

[88]  Paola Sebastiani,et al.  Early dysregulation of cell adhesion and extracellular matrix pathways in breast cancer progression. , 2009, The American journal of pathology.

[89]  A. Davidoff,et al.  Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. , 2002, Blood.

[90]  C. Eng,et al.  PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. , 1999, Cancer research.

[91]  Kornelia Polyak,et al.  Breast cancer: origins and evolution. , 2007, The Journal of clinical investigation.

[92]  Shuomin Zhu,et al.  miR-21-mediated tumor growth , 2007, Oncogene.

[93]  Hanah Margalit,et al.  Clustering and conservation patterns of human microRNAs , 2005, Nucleic acids research.

[94]  T. Litman,et al.  High expression of miR‐21 in tumor stroma correlates with increased cancer cell proliferation in human breast cancer , 2011, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[95]  Massimo Broggini,et al.  Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. , 2012, Cancer treatment reviews.

[96]  F. Orso,et al.  miR-21 coordinates tumor growth and modulates KRIT1 levels , 2013, Biochemical and biophysical research communications.

[97]  C. Croce,et al.  Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA , 2012, Proceedings of the National Academy of Sciences.

[98]  W. Loo,et al.  DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. , 2005, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[99]  K. Kajo,et al.  RASSF1A Promoter Methylation Levels Positively Correlate with Estrogen Receptor Expression in Breast Cancer Patients. , 2013, Translational oncology.

[100]  H. Sültmann,et al.  The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. , 2007, Cancer research.

[101]  Yuchuan Huang,et al.  Circulating miRNAs: promising biomarkers of human cancer. , 2011, Asian Pacific journal of cancer prevention : APJCP.

[102]  B. Kholodenko,et al.  Signalling mechanisms regulating phenotypic changes in breast cancer cells , 2015, Bioscience reports.

[103]  Xuan Pan,et al.  MicroRNA-21: A novel therapeutic target in human cancer , 2010, Cancer biology & therapy.