MicroRNAs as Novel Biomarkers for Breast Cancer

Breast cancer is a complex phenotypically diverse genetic disease, involving a variety of changes in gene expression and structure. Recent advances in molecular profiling technology have made great progress in unravelling the molecular taxonomy of breast cancer, which has shed new light on the aetiology of the disease and also heralded great potential for the development of novel biomarkers and therapeutic targets. Mi(cro)RNAs are a contemporary class of small noncoding endogenous RNA molecules, generating great excitement in the clinical and scientific communities. The recent discovery that miRNA expression is frequently dysregulated in cancer has uncovered an entirely new repertoire of molecular factors upstream of gene expression, which warrants extensive investigation to further elucidate their precise role in malignancy. We present a comprehensive and timely review of the role of miRNAs in cancer: addressing miRNA function, their putative role as oncogenes or tumor suppressors, with a particular emphasis on breast cancer throughout. We discuss the recent discovery of quantifiable circulating cancer-associated miRNAs, which heralds immense potential for their use as novel minimally invasive biomarkers for breast and other cancers. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment.

[1]  Vladimir Benes,et al.  A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). , 2006, RNA.

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

[3]  R. Bast,et al.  American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  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.

[5]  H. Horvitz,et al.  The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. , 2005, Developmental cell.

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

[7]  Martin Tabler,et al.  Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in Drosophila and the identification of putative target genes. , 2003, Nucleic acids research.

[8]  G. Hampton,et al.  Definition and refinement of chromosome 11 regions of loss of heterozygosity in breast cancer: identification of a new region at 11q23.3. , 1995, Cancer research.

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

[10]  Zhongqiu Lin,et al.  Expression profile of mammalian microRNAs in endometrioid adenocarcinoma , 2009, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

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

[12]  B. L. de Groot,et al.  Predicting free energy changes using structural ensembles , 2009, Nature Methods.

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

[14]  Luigi Naldini,et al.  Stable knockdown of microRNA in vivo by lentiviral vectors , 2009, Nature Methods.

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

[16]  N. Miller,et al.  O-7 Micro-RNA expression profiling in primary breast tumours , 2007 .

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

[18]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[19]  S. Kauppinen,et al.  LNA-modified oligonucleotides mediate specific inhibition of microRNA function. , 2006, Gene.

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

[21]  K. Livak,et al.  Multiplexing RT-PCR for the detection of multiple miRNA species in small samples. , 2006, Biochemical and biophysical research communications.

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

[23]  M. Kerin,et al.  An evaluation of preoperative CA 15-3 measurement in primary breast carcinoma. , 1995, British Journal of Cancer.

[24]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

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

[26]  J. Mendell.  miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[27]  H. Dressman,et al.  MicroRNAs and their target messenger RNAs associated with endometrial carcinogenesis. , 2008, Gynecologic oncology.

[28]  Tian-Li Wang,et al.  MicroRNA Expression and Identification of Putative miRNA Targets in Ovarian Cancer , 2008, PloS one.

[29]  S. Mok,et al.  Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong women , 2009, International journal of cancer.

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

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

[32]  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.

[33]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[34]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

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

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

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

[38]  A. Howell,et al.  Evaluation of the current knowledge limitations in breast cancer research: a gap analysis , 2008, Breast Cancer Research.

[39]  Phillip D Zamore,et al.  Sequence-Specific Inhibition of Small RNA Function , 2004, PLoS biology.

[40]  Thomas Tuschl,et al.  Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. , 2004, RNA.

[41]  Yoko Takahashi,et al.  Aberrant expression of HOX genes in human invasive breast carcinoma. , 2005, Oncology Report.

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

[43]  T. Kinoshita,et al.  Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer , 2008, International Journal of Clinical Oncology.

[44]  Richard J Jackson,et al.  How Do MicroRNAs Regulate Gene Expression? , 2007, Science's STKE.

[45]  J. Elmore,et al.  Background Methods Results , 2009 .

[46]  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.

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

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

[49]  M. Todesco,et al.  Target mimicry provides a new mechanism for regulation of microRNA activity , 2007, Nature Genetics.

[50]  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.

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

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

[53]  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.

[54]  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.