Semin Reprod Med 2008; 26(6): 522-536
DOI: 10.1055/s-0028-1096132
© Thieme Medical Publishers

Involvement of MicroRNAs in Breast Cancer

Brian D. Adams1 , 4 , Irene K. Guttilla2 , 4 , Bruce A. White3 , 4
  • 1Graduate Assistant/Student, Department of Cell Biology, Farmington, Connecticut
  • 2Graduate Assistant/Student, Department of Molecular Microbial and Structural Biology, Farmington, Connecticut
  • 3Professor, Department of Cell Biology, Farmington, Connecticut
  • 4University of Connecticut Health Center, Farmington, Connecticut
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Publikationsverlauf

Publikationsdatum:
24. Oktober 2008 (online)

ABSTRACT

MicroRNAs regulate numerous aspects of normal and pathologic cellular processes, including cancer. Breast cancer is a heterogeneous form of cancer that is derived from mammary epithelial cells. This review discusses the involvement of microRNAs in the regulation of normal mammary epithelial stem cells, their differentiation into basal and luminal phenotypes, and their control of breast cancer stem cells, also referred to as tumor-initiating cells. In the second section, we summarize the findings of differential microRNA expression in normal versus breast tumor tissue and among the various subtypes of breast cancer (primarily luminal, basal-like, and HER2). In the third and fourth sections of the review, specific mRNA targets of microRNAs in breast cancer are discussed, including those encoding the estrogen receptor-α and epidermal growth factor receptor, as well as survival, tumor suppressor, and cell-cycle–related proteins. Finally, the involvement of microRNAs in the promotion and suppression of breast cancer metastasis is reviewed. The studies presented herein provide a rationale for the design of therapeutic agents that target specific microRNAs in the treatment of breast cancer. Hopefully, this review will provide an impetus for more studies on the role of microRNAs in the regulation of normal mammary gland development and function.

REFERENCES

  • 1 Mullan P B, Millikan R C. Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.  Cell Mol Life Sci. 2007;  64 3219-3232
  • 2 Hu Z, Fan C, Oh D S et al.. The molecular portraits of breast tumors are conserved across microarray platforms.  BMC Genomics. 2006;  7 96-107
  • 3 Peppercorn J, Perou C M, Carey L A et al.. Molecular subtypes in breast cancer evaluation and management: divide and conquer.  Cancer Invest. 2008;  26 1-10
  • 4 Bushati N, Cohen S M. MicroRNA functions.  Annu Rev Cell Dev Biol. 2007;  23 175-205
  • 5 Calin G A, Croce C M. MicroRNA-cancer connection: the beginning of a new tale.  Cancer Res. 2006;  66 7390-7394
  • 6 Cho W C. OncomiRs: the discovery and progress of microRNAs in cancers.  Mol Cancer. 2007;  6 60-66
  • 7 Voorhoeve P M, Agami R. Classifying microRNAs in cancer: the good, the bad and the ugly.  Biochim Biophys Acta. 2007;  1775 274-282
  • 8 Villadsen R. In search of a stem cell hierarchy in the human breast and its relevance to breast cancer evolution.  APMIS. 2005;  113 903-921
  • 9 Dontu G, El-Ashry D, Wicha M S. Breast cancer, stem/progenitor cells and the estrogen receptor.  Trends Endocrinol Metab. 2004;  15 193-197
  • 10 Stingl J, Caldas C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis.  Nat Rev Cancer. 2007;  7 791-799
  • 11 Shackleton M, Vaillant F, Simpson K J et al.. Generation of a functional mammary gland from a single stem cell.  Nature. 2006;  439 84-88
  • 12 Proia D A, Kuperwasser C. Reconstruction of human mammary tissues in a mouse model.  Nat Protoc. 2006;  1 206-214
  • 13 Ibarra I, Erlich Y, Muthuswamy S K, Sachidanandam R, Hannon G J. A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells.  Genes Dev. 2007;  21 3238
  • 14 Sempere L F, Christensen M, Silahtaroglu A et al.. Altered microRNA expression confined to specific epithelial cell subpopulations in breast cancer.  Cancer Res. 2007;  67 11612-11620
  • 15 Dalerba P, Cho R W, Clarke M F. Cancer stem cells: models and concepts.  Annu Rev Med. 2007;  58 267-284
  • 16 Yu F, Yao H, Zhu P et al.. let-7 regulates self renewal and tumorigenicity of breast cancer cells.  Cell. 2007;  131 1109-1123
  • 17 Johnson S M, Grosshans H, Shingara J et al.. RAS is regulated by the let-7 microRNA family.  Cell. 2005;  120 635-647
  • 18 Lee Y S, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.  Genes Dev. 2007;  21 1025-1030
  • 19 Calin G A, Dumitru C D, Shimizu M et al.. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.  Proc Natl Acad Sci U S A. 2002;  99 15524-15529
  • 20 Calin G A, Sevignani C, Dumitru C D et al.. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.  Proc Natl Acad Sci U S A. 2004;  101 2999-3004
  • 21 Zhang L, Huang J, Yang N et al.. microRNAs exhibit high frequency genomic alterations in human cancer.  Proc Natl Acad Sci U S A. 2006;  103 9136-9141
  • 22 Lu J, Getz G, Miska E A et al.. MicroRNA expression profiles classify human cancers.  Nature. 2005;  435 834-838
  • 23 Jiang J, Lee E J, Gusev Y, Schmittgen T D. Real-time expression profiling of microRNA precursors in human cancer cell lines.  Nucleic Acids Res. 2005;  33 5394-5403
  • 24 Iorio M V, Ferracin M, Liu C G et al.. MicroRNA gene expression deregulation in human breast cancer.  Cancer Res. 2005;  65 7065-7070
  • 25 Volinia S, Calin G A, Liu C G et al.. A microRNA expression signature of human solid tumors defines cancer gene targets.  Proc Natl Acad Sci U S A. 2006;  103 2257-2261
  • 26 Mattie M D, Benz C C, Bowers J et al.. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies.  Mol Cancer. 2006;  5 24-37
  • 27 Hoadley K A, Weigman V J, Fan C et al.. EGFR associated expression profiles vary with breast tumor subtype.  BMC Genomics. 2007;  8 258
  • 28 Blenkiron C, Goldstein L D, Thorne N P et al.. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype.  Genome Biol. 2007;  8 R214
  • 29 Lee E J, Baek M, Gusev Y, Brackett D J, Nuovo G J, Schmittgen T D. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors.  RNA. 2008;  14 35-42
  • 30 Lanigan F, O'Connor D, Martin F, Gallagher W M. Molecular links between mammary gland development and breast cancer.  Cell Mol Life Sci. 2007;  64 3159-3184
  • 31 Clarke R B. Ovarian steroids and the human breast: regulation of stem cells and cell proliferation.  Maturitas. 2006;  54 327-334
  • 32 Heldring N, Pike A, Andersson S et al.. Estrogen receptors: how do they signal and what are their targets.  Physiol Rev. 2007;  87 905-931
  • 33 Adams B D, Furneaux H, White B A. The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ER-alpha messenger RNA and protein expression in breast cancer cell lines.  Mol Endocrinol. 2007;  21 1132-1147
  • 34 Stark A, Brennecke J, Bushati N, Russell R B, Cohen S M. Animal microRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution.  Cell. 2005;  123 1133-1146
  • 35 Tavazoie S F, Alarcon C, Oskarsson T et al.. Endogenous human microRNAs that suppress breast cancer metastasis.  Nature. 2008;  451 147-152
  • 36 Callis T E, Deng Z, Chen J F, Wang D Z. Muscling through the microRNA world.  Exp Biol Med. 2008;  233 131-138
  • 37 Hossain A, Kuo M T, Saunders G F. Mir-17–5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA.  Mol Cell Biol. 2006;  26 8191-8201
  • 38 Yan J, Tsai S Y, Tsai M J. SRC-3/AIB1: transcriptional coactivator in oncogenesis.  Acta Pharmacol Sin. 2006;  27 387-394
  • 39 Coller H A, Forman J J, Legesse-Miller A. “Myc'ed messages”: myc induces transcription of E2F1 while inhibiting its translation via a microRNA polycistron.  PLoS Genet. 2007;  3 146
  • 40 Woods K, Thomson J M, Hammond S M. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors.  J Biol Chem. 2007;  282 2130-2134
  • 41 Sylvestre Y, De Guire V, Querido E et al.. An E2F/miR-20a autoregulatory feedback loop.  J Biol Chem. 2007;  282 2135-2143
  • 42 Iaquinta P J, Lees J A. Life and death decisions by the E2F transcription factors.  Curr Opin Cell Biol. 2007;  19 649-657
  • 43 Renoir J M, Bouclier C, Seguin A, Marsaud V, Sola B. Antioestrogen-mediated cell cycle arrest and apoptosis induction in breast cancer and multiple myeloma cells.  J Mol Endocrinol. 2008;  40 101-112
  • 44 Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T. MicroRNA regulates the expression of human cytochrome P450 1B1.  Cancer Res. 2006;  66 9090-9098
  • 45 Ragavan N, Hewitt R, Cooper L J et al.. CYP1B1 expression in prostate is higher in the peripheral than in the transition zone.  Cancer Lett. 2004;  215 69-78
  • 46 Scott G K, Goga A, Bhaumik D, Berger C E, Sullivan C S, Benz C C. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b.  J Biol Chem. 2007;  282 1479-1486
  • 47 Ramasamy S, Duraisamy S, Barbashov S, Kawano T, Kharbanda S, Kufe D. The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop.  Mol Cell. 2007;  27 992-1004
  • 48 Wei X, Xu H, Kufe D. MUC1 oncoprotein stabilizes and activates estrogen receptor alpha.  Mol Cell. 2006;  21 295-305
  • 49 Si M L, Zhu S, Wu H, Lu Z, Wu F, Mo Y Y. miR-21-mediated tumor growth.  Oncogene. 2007;  26 2799-2803
  • 50 Zhu S, Si M L, Wu H, Mo Y Y. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1).  J Biol Chem. 2007;  282 14328-14336
  • 51 Frankel L B, Christoffersen N R, Jacobsen A, Lindow M, Krogh A, Lund A H. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells.  J Biol Chem. 2008;  283 1026-1033
  • 52 Corney D C, Flesken-Nikitin A, Godwin A K, Wang W, Nikitin A Y. MicroRNA-34b and microRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth.  Cancer Res. 2007;  67 8433-8438
  • 53 Raver-Shapira N, Marciano E, Meiri E et al.. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis.  Mol Cell. 2007;  26 731-743
  • 54 Chang T C, Wentzel E A, Kent O A et al.. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.  Mol Cell. 2007;  26 745-752
  • 55 Bommer G T, Gerin I, Feng Y et al.. p53-mediated activation of miRNA34 candidate tumor-suppressor genes.  Curr Biol. 2007;  17 1298-1307
  • 56 Tarasov V, Jung P, Verdoodt B et al.. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest.  Cell Cycle. 2007;  6 1586-1593
  • 57 Jansen A P, Camalier C E, Colburn N H. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis.  Cancer Res. 2005;  65 6034-6041
  • 58 Asangani I A, Rasheed S A, Nikolova D A et al.. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer.  Oncogene. 2008;  27 2128-2136
  • 59 Zannetti A, Del Vecchio S, Carriero M V et al.. Coordinate up-regulation of Sp1 DNA-binding activity and urokinase receptor expression in breast carcinoma.  Cancer Res. 2000;  60 1546-1551
  • 60 Scott G K, Mattie M D, Berger C E, Benz S C, Benz C C. Rapid alteration of microRNA levels by histone deacetylase inhibition.  Cancer Res. 2006;  66 1277-1281
  • 61 Mertens-Talcott S U, Chintharlapalli S, Li X, Safe S. The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells.  Cancer Res. 2007;  67 11001-11011
  • 62 Sleeman J P, Cremers N. New concepts in breast cancer metastasis: tumor initiating cells and the microenvironment.  Clin Exp Metastasis. 2007;  24 707-715
  • 63 Vernon A E, Bakewell S J, Chodosh L A. Deciphering the molecular basis of breast cancer metastasis with mouse models.  Rev Endocr Metab Disord. 2007;  8 199-213
  • 64 McSherry E A, Donatello S, Hopkins A M, McDonnell S. Molecular basis of invasion in breast cancer.  Cell Mol Life Sci. 2007;  64 3201-3218
  • 65 Ma L, Teruya-Feldstein J, Weinberg R A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.  Nature. 2007;  449 682-688
  • 66 Yang J, Mani S A, Weinberg R A. Exploring a new twist on tumor metastasis.  Cancer Res. 2006;  66 4549-4552
  • 67 Voorhoeve P M, le Sage C, Schrier M et al.. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.  Cell. 2006;  124 1169-1181
  • 68 Huang Q, Gumireddy K, Schrier M et al.. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis.  Nat Cell Biol. 2008;  10 202-210
  • 69 Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo Y Y. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.  Cell Res. 2008;  18 350-359
  • 70 Masterson J, O'Dea S. Posttranslational truncation of E-cadherin and significance for tumour progression.  Cells Tissues Organs. 2007;  185 175-179
  • 71 Hurteau G J, Carlson J A, Spivack S D, Brock G J. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin.  Cancer Res. 2007;  67 7972-7976
  • 72 Chang T C, Mendell J T. microRNAs in vertebrate physiology and human disease.  Annu Rev Genomics Hum Genet. 2007;  8 215-239
  • 73 Wurdinger T, Costa F F. Molecular therapy in the microRNA era.  Pharmacogenomics J. 2007;  7 297-304
  • 74 Krutzfeldt J, Rajewsky N, Braich R et al.. Silencing of microRNAs in vivo with ‘antagomirs’.  Nature. 2005;  438 685-689
  • 75 Kumar M S, Erkeland S J, Pester R E et al.. Suppression of non-small cell lung tumor development by the let-7 microRNA family.  Proc Natl Acad Sci U S A. 2008;  105 3903-3908
  • 76 Cimmino A, Calin G A, Fabbri M et al.. miR-15 and miR-16 induce apoptosis by targeting BCL2.  Proc Natl Acad Sci U S A. 2005;  102 13944-13949
  • 77 Lu Y, Thomson J M, Wong H Y, Hammond S M, Hogan B L. Transgenic over-expression of the microRNA miR-17–92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells.  Dev Biol. 2007;  310 442-453
  • 78 Matsubara H, Takeuchi T, Nishikawa E et al.. Apoptosis induction by antisense oligonucleotides against miR-17–5p and miR-20a in lung cancers overexpressing miR-17–92.  Oncogene. 2007;  26 6099-6105
  • 79 Hayashita Y, Osada H, Tatematsu Y et al.. A polycistronic microRNA cluster, miR-17–92, is overexpressed in human lung cancers and enhances cell proliferation.  Cancer Res. 2005;  65 9628-9632
  • 80 He L, Thomson J M, Hemann M T et al.. A microRNA polycistron as a potential human oncogene.  Nature. 2005;  435 828-833
  • 81 Luzi E, Marini F, Sala S C, Tognarini I, Galli G, Brandi M L. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor.  J Bone Miner Res. 2008;  23 287-295
  • 82 Wong C F, Tellam R L. MicroRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis.  J Biol Chem. 2008;  283 9836-9843
  • 83 Fabbri M, Garzon R, Cimmino A et al.. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B.  Proc Natl Acad Sci U S A. 2007;  104 15805-15810
  • 84 He A, Zhu L, Gupta N, Chang Y, Fang F. Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3–L1 adipocytes.  Mol Endocrinol. 2007;  21 2785-2794
  • 85 Landais S, Landry S, Legault P, Rassart E. Oncogenic potential of the miR-106–363 cluster and its implication in human T-cell leukemia.  Cancer Res. 2007;  67 5699-5707
  • 86 Gramantieri L, Ferracin M, Fornari F et al.. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma.  Cancer Res. 2007;  67 6092-6099
  • 87 Chang J, Nicolas E, Marks D et al.. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1.  RNA Biol. 2004;  1 106-113
  • 88 Esau C, Davis S, Murray S F et al.. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.  Cell Metab. 2006;  3 87-98
  • 89 Jopling C L, Yi M, Lancaster A M, Lemon S M, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA.  Science. 2005;  309 1577-1581
  • 90 Chen Y, Gorski D H. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5.  Blood. 2008;  111 1217-1226
  • 91 Akao Y, Nakagawa Y, Naoe T. MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers.  Oncol Rep. 2006;  16 845-850
  • 92 Taganov K D, Boldin M P, Chang K J, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.  Proc Natl Acad Sci U S A. 2006;  103 12481-12486
  • 93 Xiao C, Calado D P, Galler G et al.. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb.  Cell. 2007;  131 146-159
  • 94 Eis P S, Tam W, Sun L et al.. Accumulation of miR-155 and BIC RNA in human B cell lymphomas.  Proc Natl Acad Sci U S A. 2005;  102 3627-3632
  • 95 Gironella M, Seux M, Xie M J et al.. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development.  Proc Natl Acad Sci U S A. 2007;  104 16170-16175
  • 96 Li Q J, Chau J, Ebert P J et al.. miR-181a is an intrinsic modulator of T cell sensitivity and selection.  Cell. 2007;  129 147-161
  • 97 Meng F, Henson R, Lang M et al.. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines.  Gastroenterology. 2006;  130 2113-2129
  • 98 Yang H, Kong W, He L et al.. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.  Cancer Res. 2008;  68 425-433
  • 99 Visone R, Russo L, Pallante P et al.. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle.  Endocr Relat Cancer. 2007;  14 791-798
  • 100 Felli N, Fontana L, Pelosi E et al.. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.  Proc Natl Acad Sci U S A. 2005;  102 18081-18086
  • 101 Wang Y, Lee A T, Ma J Z et al.. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target.  J Biol Chem. 2008;  283 13205-13215

Bruce A WhitePh.D. 

Professor, Department of Cell Biology, University of Connecticut Health Center

263 Farmington Avenue, Farmington, CT 06030

eMail: BWhite@nso2.uchc.edu

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