miRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in Situ
2017; Elsevier BV; Volume: 188; Issue: 3 Linguagem: Inglês
10.1016/j.ajpath.2017.11.003
ISSN1525-2191
AutoresBethany N. Hannafon, Wei-Qun Ding,
Tópico(s)RNA modifications and cancer
ResumoDuctal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS before the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined before invasion. However, important questions remain surrounding the specific changes and processes required for malignant progression and identification of prognostic indicators of aggressiveness. miRNAs are small regulatory RNAs that can modulate gene expression by complementary binding to target mRNAs and inducing translational repression and/or mRNA degradation. In the past decade, research has shown that miRNA expression is dysregulated in IDC and that these changes are already present at the DCIS stage. Therefore, changes in miRNA expression may provide the necessary information to identify a clinical indicator of the aggressiveness of DCIS. Herein, we review the miRNA signatures identified in DCIS, describe how these signatures may be used to predict the aggressiveness of DCIS, and discuss future perspectives for DCIS biomarker discovery. Ductal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS before the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined before invasion. However, important questions remain surrounding the specific changes and processes required for malignant progression and identification of prognostic indicators of aggressiveness. miRNAs are small regulatory RNAs that can modulate gene expression by complementary binding to target mRNAs and inducing translational repression and/or mRNA degradation. In the past decade, research has shown that miRNA expression is dysregulated in IDC and that these changes are already present at the DCIS stage. Therefore, changes in miRNA expression may provide the necessary information to identify a clinical indicator of the aggressiveness of DCIS. Herein, we review the miRNA signatures identified in DCIS, describe how these signatures may be used to predict the aggressiveness of DCIS, and discuss future perspectives for DCIS biomarker discovery. Breast cancer is the most diagnosed nonskin cancer and the second leading cause of cancer death among women in the United States. Most breast cancers are invasive, meaning they have invaded through the walls of the ducts or lobules of the mammary gland, and are referred to as either invasive ductal carcinoma (IDC) or invasive lobular carcinoma, respectively. It was estimated that there were approximately 231,000 new cases of invasive breast cancer (IBC) and 60,000 additional cases of the precursor lesion carcinoma in situ in 2015.1American Cancer SocietyBreast Cancer Facts & Figures 2015-2016. American Cancer Society, Atlanta2015Google Scholar Carcinoma in situ is an abnormal proliferation of cells that appear morphologically malignant within the lumen of the mammary duct [ductal carcinoma in situ (DCIS)] or lobules [lobular carcinoma in situ (LCIS)] but have not invaded into the surrounding tissues. DCIS is the most common type of in situ breast cancer and currently accounts for 83% of all in situ diagnoses, whereas LCIS is rarer and accounts for approximately only 13%. Rates of DCIS diagnosis have dramatically increased during the past three decades, because of increased rates of screening by mammography.1American Cancer SocietyBreast Cancer Facts & Figures 2015-2016. American Cancer Society, Atlanta2015Google Scholar A woman diagnosed with DCIS is 8 to 10 times more likely to be subsequently diagnosed with IBC within her lifetime.2Lopez-Garcia M.A. Geyer F.C. Lacroix-Triki M. Marchio C. Reis-Filho J.S. Breast cancer precursors revisited: molecular features and progression pathways.Histopathology. 2010; 57: 171-192Crossref PubMed Scopus (243) Google Scholar Although diagnosis of DCIS indicates an increased risk,3Collins L.C. Tamimi R.M. Baer H.J. Connolly J.L. Colditz G.A. Schnitt S.J. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses' Health Study.Cancer. 2005; 103: 1778-1784Crossref PubMed Scopus (217) Google Scholar DCIS is widely considered a nonobligate precursor to IDC and approximately half of DCISs will not progress, even if left untreated.4Allegra C.J. Aberle D.R. Ganschow P. Hahn S.M. Lee C.N. Millon-Underwood S. Pike M.C. Reed S.D. Saftlas A.F. Scarvalone S.A. Schwartz A.M. Slomski C. Yothers G. Zon R. NIH state-of-the-science conference statement: diagnosis and management of ductal carcinoma in situ (DCIS).NIH Consens State Sci Statements. 2009; 26: 1-27PubMed Google Scholar Currently, there is no way to identify the DCIS lesions that will progress to IDC from those that will not, which often leads to aggressive and potentially unnecessary interventions, including surgery, radiation, and/or hormonal therapy. In recent years, it has been established that the molecular changes present in breast cancer tissues at the preinvasive stage5Hannafon B.N. Sebastiani P. de las Morenas A. Lu J. Rosenberg C.L. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.Breast Cancer Res. 2011; 13: R24Crossref PubMed Scopus (141) Google Scholar, 6Iorio M.V. Ferracin M. Liu C.G. Veronese A. Spizzo R. Sabbioni S. Magri E. Pedriali M. Fabbri M. Campiglio M. Menard S. Palazzo J.P. Rosenberg A. Musiani P. Volinia S. Nenci I. Calin G.A. Querzoli P. Negrini M. Croce C.M. MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3481) Google Scholar are virtually indistinguishable from the molecular changes present in IDC. In fact, most cellular and molecular changes occur in the transition from normal epithelium to DCIS.7Ma X.J. Salunga R. Tuggle J.T. Gaudet J. Enright E. McQuary P. Payette T. Pistone M. Stecker K. Zhang B.M. Zhou Y.X. Varnholt H. Smith B. Gadd M. Chatfield E. Kessler J. Baer T.M. Erlander M.G. Sgroi D.C. Gene expression profiles of human breast cancer progression.Proc Natl Acad Sci U S A. 2003; 100: 5974-5979Crossref PubMed Scopus (724) Google Scholar, 8Porter D. Lahti-Domenici J. Keshaviah A. Bae Y.K. Argani P. Marks J. Richardson A. Cooper A. Strausberg R. Riggins G.J. Schnitt S. Gabrielson E. Gelman R. Polyak K. Molecular markers in ductal carcinoma in situ of the breast.Mol Cancer Res. 2003; 1: 362-375PubMed Google Scholar It is unclear which specific cellular and molecular changes are required for progression of DCIS to IDC, and a prognostic indicator of progression has yet to be identified. miRNAs are small (17 to 22 nucleotides) noncoding RNAs that post-transcriptionally regulate gene expression through the RNA interference pathway. The biogenesis of most miRNAs involves transcription by RNA polymerase II into primary miRNAs9Cai X. Hagedorn C.H. Cullen B.R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs.RNA. 2004; 10: 1957-1966Crossref PubMed Scopus (1393) Google Scholar, 10Lee Y. Jeon K. Lee J.T. Kim S. Kim V.N. MicroRNA maturation: stepwise processing and subcellular localization.EMBO J. 2002; 21: 4663-4670Crossref PubMed Scopus (1706) Google Scholar and subsequent processing in the nucleus into shorter hairpin structures, called pre-miRNAs by the enzyme Drosha. The pre-miRNAs are then transported out of the nucleus and into the cytoplasm, where they are further processed into mature miRNAs by the enzyme Dicer.10Lee Y. Jeon K. Lee J.T. Kim S. Kim V.N. MicroRNA maturation: stepwise processing and subcellular localization.EMBO J. 2002; 21: 4663-4670Crossref PubMed Scopus (1706) Google Scholar Mature miRNAs are loaded into a ribonucleoprotein complex, called the RNA-induced silencing complex. In the canonical site-targeting process, the RNA-induced silencing complex guides the mature miRNA to a target mRNA, where sequence-specific binding to the 3′-untranslated region occurs. The binding results in either translational inhibition or mRNA degradation.11Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (15899) Google Scholar The most recent update of miRBase (http://www.miRBase.org, last accessed September 27, 2017) has cataloged 1881 human miRNA genes that produce 2588 mature miRNAs.12Griffiths-Jones S. miRBase: the microRNA sequence database.Methods Mol Biol. 2006; 342: 129-138Crossref PubMed Scopus (538) Google Scholar A single miRNA may regulate thousands of mRNAs; likewise, a single mRNA may be targeted by hundreds of miRNAs, establishing miRNAs as the largest class of gene regulators.13Lim L.P. Lau N.C. Garrett-Engele P. Grimson A. Schelter J.M. Castle J. Bartel D.P. Linsley P.S. Johnson J.M. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.Nature. 2005; 433: 769-773Crossref PubMed Scopus (3999) Google Scholar Through this mechanism, miRNAs have become important factors involved in the regulation of most cellular and developmental processes.14Taft R.J. Pang K.C. Mercer T.R. Dinger M. Mattick J.S. Non-coding RNAs: regulators of disease.J Pathol. 2010; 220: 126-139Crossref PubMed Scopus (844) Google Scholar Likewise, because of their broad regulatory activity, miRNAs are involved in many pathologic processes, including cancer development and progression.15Melo S.A. Esteller M. Dysregulation of microRNAs in cancer: playing with fire.FEBS Lett. 2011; 585: 2087-2099Crossref PubMed Scopus (255) Google Scholar In the context of cancer, miRNAs may function as either tumor suppressors or oncogenes and assist in the promotion or suppression of cancer growth and progression. Aberrant miRNA expression has been described across many cancer types, including breast cancer, with global down-regulation of miRNA expression seen as a common trend.16Lu J. Getz G. Miska E.A. Alvarez-Saavedra E. Lamb J. Peck D. Sweet-Cordero A. Ebert B.L. Mak R.H. Ferrando A.A. Downing J.R. Jacks T. Horvitz H.R. Golub T.R. MicroRNA expression profiles classify human cancers.Nature. 2005; 435: 834-838Crossref PubMed Scopus (8221) Google Scholar, 17Guo Y. Chen Z. Zhang L. Zhou F. Shi S. Feng X. Li B. Meng X. Ma X. Luo M. Shao K. Li N. Qiu B. Mitchelson K. Cheng J. He J. Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma.Cancer Res. 2008; 68: 26-33Crossref PubMed Scopus (318) Google Scholar The first indication that miRNAs may be involved in cancer promotion was the discovery that miR-15 and miR-16 are deleted in most (68%) patients with B-cell chronic lymphocytic leukemia18Calin G.A. Dumitru C.D. Shimizu M. Bichi R. Zupo S. Noch E. Aldler H. Rattan S. Keating M. Rai K. Rassenti L. Kipps T. Negrini M. Bullrich F. Croce C.M. 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: 15524-15529Crossref PubMed Scopus (4229) Google Scholar and that miRNA genes are commonly found at fragile sites in the genome, which are frequently lost, mutated, amplified, or rearranged.19Calin G.A. Sevignani C. Dumitru C.D. Hyslop T. Noch E. Yendamuri S. Shimizu M. Rattan S. Bullrich F. Negrini M. Croce C.M. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.Proc Natl Acad Sci U S A. 2004; 101: 2999-3004Crossref PubMed Scopus (3575) Google Scholar Since these initial studies, a plethora of research using loss-of-function and gain-of-function approaches in human cancer cells, mouse xenografts, transgenic mouse models, and knockout mouse models has demonstrated that miRNAs play key roles in all of the common hallmarks of cancer, including initiation, progression, and metastasis.20Iorio M.V. Croce C.M. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics: a comprehensive review.EMBO Mol Med. 2012; 4: 143-159Crossref PubMed Scopus (1306) Google Scholar The first study to demonstrate the power of miRNA expression analysis in cancer tissues showed that miRNA profiling of just 217 miRNAs across >300 cancer specimens may distinguish tumor tissues from normal tissues and classify tumors by common origin and unknown origin; it also showed that miRNAs classified tumors better than expression profiling of >16,000 mRNAs.16Lu J. Getz G. Miska E.A. Alvarez-Saavedra E. Lamb J. Peck D. Sweet-Cordero A. Ebert B.L. Mak R.H. Ferrando A.A. Downing J.R. Jacks T. Horvitz H.R. Golub T.R. MicroRNA expression profiles classify human cancers.Nature. 2005; 435: 834-838Crossref PubMed Scopus (8221) Google Scholar The first study to examine miRNA expression changes in IBC measured 245 miRNAs by microarray analysis in 76 breast tumor tissues and pooled normal tissues. This study showed that miRNA expression is deregulated in IBC, with miR-10b, miR-125b, miR-145 being the most significantly down-regulated and miR-21 and miR-155 being the most significantly up-regulated. This miRNA profile can distinguish IBC tissues from normal tissues and correlated with pathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index. Furthermore, a distinct miRNA signature was identified in luminal IBC, with up-regulation of miR-191 and miR-26 and down-regulation of miR-206.6Iorio M.V. Ferracin M. Liu C.G. Veronese A. Spizzo R. Sabbioni S. Magri E. Pedriali M. Fabbri M. Campiglio M. Menard S. Palazzo J.P. Rosenberg A. Musiani P. Volinia S. Nenci I. Calin G.A. Querzoli P. Negrini M. Croce C.M. MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3481) Google Scholar The first integrative molecular analysis by Blenkiron et al21Blenkiron C. Goldstein L.D. Thorne N.P. Spiteri I. Chin S.F. Dunning M.J. Barbosa-Morais N.L. Teschendorff A.E. Green A.R. Ellis I.O. Tavare S. Caldas C. Miska E.A. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype.Genome Biol. 2007; 8: R214Crossref PubMed Scopus (802) Google Scholar examined miRNA expression, mRNA expression, and genomic changes in breast cancer in 93 primary tumors, 21 cell lines, and 5 normal samples. Using a bead-based flow-cytometric miRNA profiling method, this study demonstrated that miRNAs may classify breast tumors by their molecular subtypes, such as luminal A, luminal B, basal-like, human epidermal growth factor receptor 2+, and normal like, and were associated with certain clinicopathological features. Specifically, a set of nine miRNAs (miR-100, miR-99a, miR-130a, miR-126, miR-136, miR-146b, miR-15b, miR-107, and miR-103) can distinguish luminal A from luminal B tumors. In addition, the changes in miRNA expression were somewhat explained by correlative changes in DNA copy number gains or losses.21Blenkiron C. Goldstein L.D. Thorne N.P. Spiteri I. Chin S.F. Dunning M.J. Barbosa-Morais N.L. Teschendorff A.E. Green A.R. Ellis I.O. Tavare S. Caldas C. Miska E.A. MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype.Genome Biol. 2007; 8: R214Crossref PubMed Scopus (802) Google Scholar These studies have established that miRNA expression is altered in IBC tissue compared with normal tissues. Numerous studies have followed that provide further evidence to refine the concept that miRNA signatures have great potential to serve as biomarkers of breast cancer, for detecting the tumor at an early stage, further classifying breast cancer subtypes, and monitoring therapeutic responses.22Amorim M. Salta S. Henrique R. Jeronimo C. Decoding the usefulness of non-coding RNAs as breast cancer markers.J Transl Med. 2016; 14: 265Crossref PubMed Scopus (43) Google Scholar The first study to look specifically at miRNA expression changes in breast epithelial cells profiled miRNAs in normal tissues, IBC tumor tissues, and cell lines, and confirmed their results by fluorescent in situ hybridization on formalin-fixed, paraffin-embedded normal and matching tumor tissue specimens. The expression of miR-145 and miR-205 was confined to the myoepithelial cell layer in normal tissues and lost in the matching tumor specimens, whereas expression of let-7a, miR-21, miR-141, and miR-214 was confined to the luminal epithelial cell layer. This study also identified early aberrant miR-145 expression in atypical ductal hyperplasia (ADH), an intermediate stage of preinvasive breast cancer, and DCIS lesions.23Sempere L.F. Christensen M. Silahtaroglu A. Bak M. Heath C.V. Schwartz G. Wells W. Kauppinen S. Cole C.N. Altered microRNA expression confined to specific epithelial cell subpopulations in breast cancer.Cancer Res. 2007; 67: 11612-11620Crossref PubMed Scopus (497) Google Scholar The first study to specifically examine the molecular changes in breast epithelial cells from preinvasive DCIS tissues used an integrative approach to profile both the miRNA expression by quantitative RT-PCR and mRNA expression by microarray. This was performed in epithelial cells microdissected from normal tissues obtained from reduction mammoplasty (n = 9) procedures from women with no history of cancer and paired samples of histologically normal (n = 8) and DCIS (n = 8). Thirty-five miRNAs were differentially expressed among the three groups, with 29 miRNAs differentially expressed, 15 miRNAs overexpressed, and 14 miRNAs underexpressed, between DCIS and histologically normal samples (Table 1). Of these miRNAs, 18 of 29 (62%) were previously implicated in IBC, and concordant with the earlier reports,6Iorio M.V. Ferracin M. Liu C.G. Veronese A. Spizzo R. Sabbioni S. Magri E. Pedriali M. Fabbri M. Campiglio M. Menard S. Palazzo J.P. Rosenberg A. Musiani P. Volinia S. Nenci I. Calin G.A. Querzoli P. Negrini M. Croce C.M. MicroRNA gene expression deregulation in human breast cancer.Cancer Res. 2005; 65: 7065-7070Crossref PubMed Scopus (3481) Google Scholar this showed that many miRNA expression changes are present in DCIS before the development of IBC. Interestingly, 11 miRNAs were differentially expressed between the reduction mammoplasty and histologically normal samples, indicating that miRNA expression changes are present in normal-appearing tissues before the emergence of neoplasia. Examination of the mRNA expression profiles from these same tissue samples showed that 420 mRNAs were differentially expressed among the histologically normal and DCIS samples. The miRNA and mRNA expression profiles were integrated with miRNA target prediction, with 113 miRNA/mRNA functional pairs identified with high confidence. Several target pairs were validated in breast cancer cell lines in vitro, and inhibition of miR-182 (highly expressed in DCIS) increased expression of chromobox 7 and E-cadherin (positively regulated by chromobox 7), which is generally lost during breast cancer progression.5Hannafon B.N. Sebastiani P. de las Morenas A. Lu J. Rosenberg C.L. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.Breast Cancer Res. 2011; 13: R24Crossref PubMed Scopus (141) Google ScholarTable 1Summary of miRNA Expression Profiling Studies in Preinvasive Breast CancerSample typeAnalysis methodMajor findingsmiRNA expression∗Fold change ≥1.5.ReferenceNormal-ADHNormal-DCISDCIS-IBCMicrodissected epithelial cells: RM (n = 9), paired normal (n = 8) and DCIS (n = 8)RT-qPCR, TaqMan low-density array99 miRNAs were differentially expressed between DCIS and normal mammary epithelial cells↑miR-7↑miR-18a↑miR-21↑miR-93↑miR-99b↑mir-181b↑miR-182↑miR-183↑miR-191↑miR-193b↑miR-200b/c↑miR-324-5p↑miR-365↑miR-425-5p↑miR-449b↓let-7c↓miR-10b↓miR-99a↓mir-125b↓miR-127↓miR-130a↓miR-145↓miR-195↓miR-204↓miR-376a↓miR-382↓miR-410↓miR-511Hannafon et al5Hannafon B.N. Sebastiani P. de las Morenas A. Lu J. Rosenberg C.L. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer.Breast Cancer Res. 2011; 13: R24Crossref PubMed Scopus (141) Google ScholarBulk extracted tissues: normal (n = 11), DCIS (n = 17), IBC (n = 151)Solexa (Cambridge, UK) next-generation sequencing (in house)Normal breast tissues may be distinguished from DCIS and IBC by increased miR-21 and decreased miR-98 and let-7 levels; most changes in miRNA expression already present in DCIS↑miR-21↑miR-142-3p↑miR-142-5p↓miR-22↓miR-98 cluster (miR-125a, miR-99a, let-7a)↓miR-451↓miR-144↓miR-143*↓miR-320↓miR-378↓miR-497↑miR-142-3p↓miR-125a↓miR-451↓miR-144↓miR-145↓miR-143↓miR-378Farazi et al24Farazi T.A. Horlings H.M. Ten Hoeve J.J. Mihailovic A. Halfwerk H. Morozov P. Brown M. Hafner M. Reyal F. van Kouwenhove M. Kreike B. Sie D. Hovestadt V. Wessels L.F. van de Vijver M.J. Tuschl T. MicroRNA sequence and expression analysis in breast tumors by deep sequencing.Cancer Res. 2011; 71: 4443-4453Crossref PubMed Scopus (315) Google ScholarSubset of samples from Farazi et al, 201124Farazi T.A. Horlings H.M. Ten Hoeve J.J. Mihailovic A. Halfwerk H. Morozov P. Brown M. Hafner M. Reyal F. van Kouwenhove M. Kreike B. Sie D. Hovestadt V. Wessels L.F. van de Vijver M.J. Tuschl T. MicroRNA sequence and expression analysis in breast tumors by deep sequencing.Cancer Res. 2011; 71: 4443-4453Crossref PubMed Scopus (315) Google Scholar: normal (n = 6), DCIS (n = 8), IBC (n = 80)Reanalysis of Solexa next-generation sequencing-used only the most reliable results66 miRNAs were deregulated in the normal-DCIS†Top 12 differentially expressed miRNAs are listed. transition, whereas only nine were different between the DCIS-IBC transition; most changes in miRNA expression already present in DCIS↑miR-21↑miR-200c↑miR-16↑miR-142-5p/3p↑miR-374a↑miR-26b↑miR-29b↑miR-183↑miR-96↑miR-106b↑miR-182↑miR-361-5p↓miR-320↓miR-378↓miR-127-3p↓let-7b, c, d↓miR-376a/c↓miR-193a/b↓miR-99a↓miR-22↓miR-423-5p↓miR-145↓miR-125b↓miR-497↑let-7d↑miR-181a↑miR-210↑miR-221↓miR-10b↓miR-126↓miR-143↓miR-218↓miR-335-5pVolinia et al25Volinia S. Galasso M. Sana M.E. Wise T.F. Palatini J. Huebner K. Croce C.M. Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA.Proc Natl Acad Sci U S A. 2012; 109: 3024-3029Crossref PubMed Scopus (308) Google ScholarLaser capture–microdissected FFPE tissues: normal (n = 8), ADH (n = 4), DCIS (n = 6), IBC (n = 7)miRNA microarray↑miR-21↑miR-200b↑miR-15b↑miR-183↑miR-30d↓miR-1275↓miR-638↓miR-572↓miR-671-5p↑miR-556-3p↓miR-557↓miR-1207-5p↓miR-874Chen et al26Chen L. Li Y. Fu Y. Peng J. Mo M.H. Stamatakos M. Teal C.B. Brem R.F. Stojadinovic A. Grinkemeyer M. McCaffrey T.A. Man Y.G. Fu S.W. Role of deregulated microRNAs in breast cancer progression using FFPE tissue.PLoS One. 2013; 8: e54213Crossref PubMed Scopus (85) Google ScholarBulk-extracted fresh-frozen tissues: normal (n = 186), DCIS (n = 18), IBC (n = 1338)miRNA microarray70 miRNAs were deregulated from normal-to-DCIS tissues; no miRNAs were deregulated in DCIS-to-IBC transition; breast cancer subtype–specific miRNA expression patterns were observed↑miR-21-5p↑miR-96-5p↑miR-106b-5p↑miR-142-5p/3p↑miR-155-5p↑miR-183-5p↑miR-200b/c-3p↑miR-342-3p↑miR-425-5p↑miR-429-3p↓let-7b/c-5p↓miR-22-3p↓miR-99a-5p↓miR-100-5p↓miR-125b-5p↓miR-140-3p↓miR-143-5p↓miR-145-5p/3p↓miR-193a-5p↓miR-193b-3p↓miR-378a-3p↓miR-497-5p↓miR-652-3p↑miR-106b-5p↑miR-142↑miR-342-3p↑miR-425-5p↓let-7c-5p↓miR-125b-5p↓miR-140-3p↓miR-145-5p/3p↓miR-193a-5p↓miR-378a-3pHaakensen et al27Haakensen V.D. Nygaard V. Greger L. Aure M.R. Fromm B. Bukholm I.R. Luders T. Chin S.F. Git A. Caldas C. Kristensen V.N. Brazma A. Borresen-Dale A.L. Hovig E. Helland A. Subtype-specific micro-RNA expression signatures in breast cancer progression.Int J Cancer. 2016; 139: 1117-1128Crossref PubMed Scopus (46) Google Scholar↑, Increased; ↓, decreased; ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ; FFPE, formalin-fixed, paraffin-embedded; IBC, invasive breast cancer; RM, reduction mammoplasty; RT-qPCR, quantitative RT-PCR.∗ Fold change ≥1.5.† Top 12 differentially expressed miRNAs are listed. Open table in a new tab ↑, Increased; ↓, decreased; ADH, atypical ductal hyperplasia; DCIS, ductal carcinoma in situ; FFPE, formalin-fixed, paraffin-embedded; IBC, invasive breast cancer; RM, reduction mammoplasty; RT-qPCR, quantitative RT-PCR. Next-generation deep sequencing was used to develop a more comprehensive miRNA expression profile of normal (n = 11), DCIS (n = 17), and IBC (n = 151) specimens.24Farazi T.A. Horlings H.M. Ten Hoeve J.J. Mihailovic A. Halfwerk H. Morozov P. Brown M. Hafner M. Reyal F. van Kouwenhove M. Kreike B. Sie D. Hovestadt V. Wessels L.F. van de Vijver M.J. Tuschl T. MicroRNA sequence and expression analysis in breast tumors by deep sequencing.Cancer Res. 2011; 71: 4443-4453Crossref PubMed Scopus (315) Google Scholar Overall, normal breast tissues may be distinguished from DCIS and IBC tissues by increased miR-21 expression and decreased levels of multiple miRNAs, including miR-98 and let-7, with most changes in miRNA expression already apparent in the DCIS samples. In addition, miR-423 and miR-375 levels were higher in patients who developed metastases, and triple-negative breast cancers may be distinguished from other tumor subtypes by increased expression of the miR-17 to miR-92 cluster. A reanalysis of this next-generation sequencing data by excluding those with low-complexity runs and including only a subset of samples with the most reliable sequencing results, from normal (n = 6), DCIS (n = 8), and IBC (n = 80) samples,25Volinia S. Galasso M. Sana M.E. Wise T.F. Palatini J. Huebner K. Croce C.M. Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA.Proc Natl Acad Sci U S A. 2012; 109: 3024-3029Crossref PubMed Scopus (308) Google Scholar showed that 66 miRNAs were deregulated in the normal-to-DCIS transition (Table 126Chen L. Li Y. Fu Y. Peng J. Mo M.H. Stamatakos M. Teal C.B. Brem R.F. Stojadinovic A. Grinkemeyer M. McCaffrey T.A. Man Y.G. Fu S.W. Role of deregulated microRNAs in breast cancer progression using FFPE tissue.PLoS One. 2013; 8: e54213Crossref PubMed Scopus (85) Google Scholar, 27Haakensen V.D. Nygaard V. Greger L. Aure M.R. Fromm B. Bukholm I.R. Luders T. Chin S.F. Git A. Caldas C. Kristensen V.N. Brazma A. Borresen-Dale A.L. Hovig E. Helland A. Subtype-specific micro-RNA expression signatures in breast cancer progression.Int J Cancer. 2016; 139: 1117-1128Crossref PubMed Scopus (46) Google Scholar), whereas only 9 were changed on DCIS-to-IBC transition. This, again, demonstrated that most changes in miRNA expression were already present in the DCIS samples. The study also examined breast cancer subtype–specific miRNA expression changes and found that certain miRNAs exhibited subtype-specific expression patterns, including increased expression of miR-190b in estrogen receptor–positive/human epidermal growth factor receptor 2− disease and decreased expression of miR-96 and miR-148a in estrogen receptor–positive/human epidermal growth factor receptor 2+ disease. The most reliable subtype-specific changes occurred in triple-negative tumors, with increased expression of the miR-17 to miR-92 cluster, miR-15/16, miR-128, and miR-200c and decreased expression of miR-143/145 and miR-199b. The association of clinical parameters and miRNA expression was also assessed, including time to metastasis, which was associated with miR-127-3p, miR-210, miR-185, miR-143*, and let-7b, whereas overall survival was associated with miR-210, miR-221, and miR-652. In addition, expression of miR-210, miR-21, miR-106b*, miR-197, and let-7i correlated with both parameters.25Volinia S. Galasso M. Sana M.E. Wise T.F. Palatini J. Huebner K. Croce C.M. Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA.Proc Natl Acad Sci U S A. 2012; 109: 3024-3029Crossref PubMed Scopus (308) Google Scholar Proliferative breast lesions, such as ADH, represent an intermediate stage of preinvasive ductal breast cancer that possesses many of the same cytologic and architectural features of DCIS, but may or may not progress to DCIS and IBC. Similar to DCIS, diagnosis of ADH increases the relative risk of developing breast cancer; however, only approximately 15% of patients with ADH will progress to invasive disease.28Hartmann L.C. Sellers T.A. Frost M.H. Lingle W.L. Degnim A.C. Ghosh K. Vierkant R.A. Maloney S.D. Pankratz V.S. Hillman D.W. Suman V.J. Johnson J. Blake C. Tlsty T. Vachon C.M. Melton 3rd, L.J. Visscher D.W. Benign breast disease and the risk of breast cancer.N Engl J Med. 2005; 353: 229-237Crossref PubMed Scopus (666) Google Scholar, 29Degnim A.C. Visscher D.W. Berman H.K. Frost M.H. Sellers T.A. Vierkant R.A. Maloney S.D. Pankratz V.S. de Groen P.C. Lingle W.L. Ghosh K. Penheiter L. Tlsty T. Melton 3rd, L.J. Reynolds C.A. Hartmann L.C. Stratification of breast cancer risk in women with atypia: a Mayo cohort study.J Clin Oncol. 2007; 25: 2671-2677Crossref PubMed Scopus (206) Google Scholar To determine how early changes in miRNA expression occur in proliferative breast disease, Chen et al26Chen L. Li Y. Fu Y. Peng J. Mo M.H. Stamatakos M. Teal C.B. Brem R.F. Stojadinovic A. Grinkemeyer M. McCaffrey T.A. Man Y.G. Fu S.W. Role of deregulated microRNAs in breast cancer progression using FFPE tissue.PLoS One. 2013; 8: e54213Crossref PubMed Scopus (85) Google Scholar an
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