miRNA Biomarkers in Breast Cancer Detection and Management

Breast cancer is considered as a heterogeneous disease comprising various types of neoplasms, which involves different profile changes in both mRNA and micro-RNA (miRNA) expression. Extensive studies on mRNA expression in breast tumor have yielded some very interesting findings, some of which have been validated and used in clinic. Recent miRNA research advances showed great potential for the development of novel biomarkers and therapeutic targets. miRNAs are a new class of small non-coding regulatory RNAs that are involved in regulating gene expression at the posttranscriptional level. It has been demonstrated that miRNA expression is frequently deregulated in breast cancer, which warrants further in-depth investigation to decipher their precise regulatory role in tumorigenesis. We address briefly the regulatory mechanism of miRNA, the expression of miRNAs in tumorigenesis, and their potential use as breast cancer biomarkers for early disease diagnosis and prognosis. In addition, we discuss the use of the Formalin-Fixed, Paraffin-Embedded (FFPE) tissue as an invaluable source for breast cancer biomarker discovery and validation, and the potential use of circulating miRNAs in blood for early breast cancer detection. We envision the potential use of miRNAs in breast cancer management in the near future, particularly in improving the early diagnosis, prognosis and treatment.

[1]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[2]  Wei Xiong,et al.  MicroRNA-125b Confers the Resistance of Breast Cancer Cells to Paclitaxel through Suppression of Pro-apoptotic Bcl-2 Antagonist Killer 1 (Bak1) Expression* , 2010, The Journal of Biological Chemistry.

[3]  C. Llave,et al.  Cleavage of Scarecrow-like mRNA Targets Directed by a Class of Arabidopsis miRNA , 2002, Science.

[4]  C. Benz,et al.  Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies , 2006, Molecular Cancer.

[5]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[7]  Leonard D. Goldstein,et al.  MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype , 2007, Genome Biology.

[8]  J. Weiler,et al.  Regulating the regulators: mechanisms controlling the maturation of microRNAs. , 2009, Trends in biotechnology.

[9]  Stephen P Finn,et al.  Potential role of miR-9 and miR-223 in recurrent ovarian cancer , 2008, Molecular Cancer.

[10]  R. Stallings,et al.  MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells , 2007, Oncogene.

[11]  Terry Hyslop,et al.  A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation , 2008, The Journal of cell biology.

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

[13]  Peter Schirmacher,et al.  MicroRNA gene expression profile of hepatitis C virus–associated hepatocellular carcinoma , 2007, Hepatology.

[14]  Jean-Philippe Brunet,et al.  The melanocyte differentiation program predisposes to metastasis after neoplastic transformation , 2005, Nature Genetics.

[15]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[16]  Domenico Coppola,et al.  MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA , 2008, Molecular and Cellular Biology.

[17]  Y. Pilpel,et al.  p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC , 2010, Cell Death and Differentiation.

[18]  Y. Nakamura,et al.  Allelotype of colorectal carcinomas. , 1989, Science.

[19]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[20]  V. Ambros,et al.  Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation , 2004, Genome Biology.

[21]  B. Vogelstein,et al.  Clonal analysis of human colorectal tumors. , 1987, Science.

[22]  A. Harris,et al.  Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma , 2008, British journal of haematology.

[23]  I. Fidler,et al.  Metastasis results from preexisting variant cells within a malignant tumor. , 1977, Science.

[24]  Tyler E. Miller,et al.  MicroRNA-221/222 Confers Tamoxifen Resistance in Breast Cancer by Targeting p27Kip1*♦ , 2008, Journal of Biological Chemistry.

[25]  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.

[26]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[27]  N. Miller,et al.  Evaluation and validation of candidate endogenous control genes for real-time quantitative PCR studies of breast cancer , 2007, BMC Molecular Biology.

[28]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[29]  N. Miller,et al.  Identification of suitable endogenous control genes for microRNA gene expression analysis in human breast cancer , 2008, BMC Molecular Biology.

[30]  R. Aharonov,et al.  MicroRNAs accurately identify cancer tissue origin , 2008, Nature Biotechnology.

[31]  Michael J Kerin,et al.  MicroRNAs as Prognostic Indicators and Therapeutic Targets: Potential Effect on Breast Cancer Management , 2008, Clinical Cancer Research.

[32]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[33]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[34]  Yariv Yogev,et al.  Serum MicroRNAs Are Promising Novel Biomarkers , 2008, PloS one.

[35]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

[36]  Yi Tie,et al.  Downregulation of CCND1 and CDK6 by miR‐34a induces cell cycle arrest , 2008, FEBS letters.

[37]  P. Nowell The clonal evolution of tumor cell populations. , 1976, Science.

[38]  Duan Ma,et al.  The cell growth suppressor, mir-126, targets IRS-1. , 2008, Biochemical and biophysical research communications.

[39]  Shingo Takagi,et al.  MicroRNA regulates the expression of human cytochrome P450 1B1. , 2006, Cancer research.

[40]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[41]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Lin Zhang,et al.  The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis , 2008, Nature Cell Biology.

[43]  Stefano Volinia,et al.  MicroRNA expression profiling of male breast cancer , 2009, Breast Cancer Research.

[44]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[45]  J. Haerting,et al.  Gene-expression signatures in breast cancer. , 2003, The New England journal of medicine.

[46]  Hiroyuki Tagawa,et al.  Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. , 2004, Cancer research.

[47]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[48]  V. Beneš,et al.  Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. , 2009, Cancer research.

[49]  Robert A. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer (Nature (2007) 449, (682-688)) , 2008 .

[50]  Unlocking pathology archives for microRNA-profiling. , 2008, Anticancer research.

[51]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[52]  I. Fidler,et al.  Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. , 1990, Cancer research.

[53]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[54]  S. Schokrpur,et al.  Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells , 2008, Oncogene.

[55]  F. Yu,et al.  Tumor Invasion and Metastasis Initiated by mir-106b in Breast Cancer by Targeting BRMS1 and RB. , 2009 .

[56]  T. Sørlie,et al.  Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms , 2006, BMC Genomics.

[57]  S. Varambally,et al.  Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer , 2008, Science.

[58]  K. Hillan,et al.  Unlocking the archive – gene expression in paraffin‐embedded tissue , 2001, The Journal of pathology.

[59]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[60]  H. McLeod,et al.  Cytochrome P450 CYP1B1 over-expression in primary and metastatic ovarian cancer , 2001, British Journal of Cancer.

[61]  S. Elledge,et al.  Dicer is essential for mouse development , 2003, Nature Genetics.

[62]  C. Novina,et al.  Not miR-ly small RNAs: big potential for microRNAs in therapy. , 2008, The Journal of allergy and clinical immunology.

[63]  B. White,et al.  The Micro-Ribonucleic Acid (miRNA) miR-206 Targets the Human Estrogen Receptor-α (ERα) and Represses ERα Messenger RNA and Protein Expression in Breast Cancer Cell Lines , 2007 .

[64]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[65]  J. Lieberman,et al.  miR-200 Enhances Mouse Breast Cancer Cell Colonization to Form Distant Metastases , 2009, PloS one.

[66]  B. White,et al.  The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. , 2007, Molecular endocrinology.

[67]  Jason H. Moore,et al.  Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. , 2007, Cancer research.

[68]  Shuomin Zhu,et al.  MicroRNA-21 targets tumor suppressor genes in invasion and metastasis , 2008, Cell Research.

[69]  Stephen Safe,et al.  The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. , 2007, Cancer research.

[70]  R. Weinberg,et al.  A Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis Accessed Terms of Use Detailed Terms a Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis , 2022 .

[71]  E. Miska,et al.  MicroRNA—implications for cancer , 2007, Virchows Archiv.

[72]  Hailong Wu,et al.  p53 represses c-Myc through induction of the tumor suppressor miR-145 , 2009, Proceedings of the National Academy of Sciences.

[73]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[74]  Ligang Wu,et al.  MicroRNAs direct rapid deadenylation of mRNA. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[76]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[77]  T. Nielsen,et al.  Deconstructing the molecular portrait of basal-like breast cancer. , 2006, Trends in molecular medicine.

[78]  C. Croce,et al.  MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[79]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[80]  Eugene Berezikov,et al.  Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. , 2006, Genome research.

[81]  Hailong Wu,et al.  Suppression of cell growth and invasion by miR-205 in breast cancer , 2008, Cell Research.

[82]  David P. Bartel,et al.  Supporting Online Material Materials and Methods Fig. S1 Tables S1 and S2 References Database S1 Disrupting the Pairing between Let-7 and Hmga2 Enhances Oncogenic Transformation , 2022 .

[83]  Kazuhiko Hayashi,et al.  Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. , 2007, RNA.

[84]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[85]  R. Aharonov,et al.  Identification of hundreds of conserved and nonconserved human microRNAs , 2005, Nature Genetics.

[86]  George A. Calin,et al.  Mammalian microRNAs: a small world for fine-tuning gene expression , 2006, Mammalian Genome.

[87]  Anwar Hossain,et al.  Mir-17-5p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB1 mRNA , 2006, Molecular and Cellular Biology.

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

[89]  F. Slack,et al.  A truth serum for cancer — microRNAs have major potential as cancer biomarkers , 2008, Cell Research.

[90]  Michael F. Clarke,et al.  Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells , 2009, Cell.

[91]  Peter A. Jones,et al.  Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. , 2006, Cancer cell.

[92]  T. Davison,et al.  MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma , 2007, Oncogene.

[93]  Robert A. Weinberg,et al.  A Pleiotropically Acting MicroRNA, miR-31, Inhibits Breast Cancer Metastasis , 2009 .

[94]  T A Hughes,et al.  Small is beautiful: microRNAs and breast cancer—where are we now? , 2008, The Journal of pathology.

[95]  M. Monden,et al.  Analysis of chemical modification of RNA from formalin-fixed samples and optimization of molecular biology applications for such samples. , 1999, Nucleic acids research.

[96]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[97]  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.

[98]  G. Lutz,et al.  Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice , 2008, BMC biotechnology.

[99]  C. Benz,et al.  Coordinate Suppression of ERBB2 and ERBB3 by Enforced Expression of Micro-RNA miR-125a or miR-125b* , 2007, Journal of Biological Chemistry.

[100]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.