{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:57:37Z","timestamp":1791863857389,"version":"4.3.4"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T00:00:00Z","timestamp":1243468800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and\/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-9-163","type":"journal-article","created":{"date-parts":[[2009,5,28]],"date-time":"2009-05-28T19:17:11Z","timestamp":1243538231000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":189,"title":["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"],"prefix":"10.1186","volume":"9","author":[{"given":"Liqiang","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Bart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu Ping","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Platteel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tineke van der","family":"Sluis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sippie","family":"Huitema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Hollema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke van den","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,5,28]]},"reference":[{"key":"1497_CR1","volume-title":"World Health Organization classification of tumors of pathology and genetics, tumors of the breast and female genital organs","author":"FADP Tavassoli","year":"2003","unstructured":"Tavassoli FADP: World Health Organization classification of tumors of pathology and genetics, tumors of the breast and female genital organs. 2003, Lyon: IARC Press"},{"key":"1497_CR2","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1186\/bcr625","volume":"5","author":"SJ Schnitt","year":"2003","unstructured":"Schnitt SJ: The diagnosis and management of pre-invasive breast disease: flat epithelial atypia \u2013 classification, pathologic features and clinical significance. Breast Cancer Res. 2003, 5: 263-268. 10.1186\/bcr625.","journal-title":"Breast Cancer Res"},{"key":"1497_CR3","first-page":"223","volume":"11","author":"V Eusebi","year":"1994","unstructured":"Eusebi V, Feudale E, Foschini MP, Micheli A, Conti A, Riva C, et al: Long-term follow-up of in situ carcinoma of the breast. Semin Diagn Pathol. 1994, 11: 223-235.","journal-title":"Semin Diagn Pathol"},{"key":"1497_CR4","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1200\/JCO.2001.19.8.2263","volume":"19","author":"N Bijker","year":"2001","unstructured":"Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C, et al: Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol. 2001, 19: 2263-2271.","journal-title":"J Clin Oncol"},{"key":"1497_CR5","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1002\/(SICI)1097-0142(20000501)88:9<2072::AID-CNCR13>3.0.CO;2-H","volume":"88","author":"F Moinfar","year":"2000","unstructured":"Moinfar F, Man YG, Bratthauer GL, Ratschek M, Tavassoli FA: Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (\"clinging ductal carcinoma in situ\"): a simulator of normal mammary epithelium. Cancer. 2000, 88: 2072-2081. 10.1002\/(SICI)1097-0142(20000501)88:9<2072::AID-CNCR13>3.0.CO;2-H.","journal-title":"Cancer"},{"key":"1497_CR6","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/modpathol.3800538","volume":"19","author":"DJ Dabbs","year":"2006","unstructured":"Dabbs DJ, Carter G, Fudge M, Peng Y, Swalsky P, Finkelstein S: Molecular alterations in columnar cell lesions of the breast. Mod Pathol. 2006, 19: 344-349. 10.1038\/modpathol.3800538.","journal-title":"Mod Pathol"},{"key":"1497_CR7","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1097\/01.pas.0000157295.93914.3b","volume":"29","author":"PT Simpson","year":"2005","unstructured":"Simpson PT, Gale T, Reis-Filho JS, Jones C, Parry S, Sloane JP, et al: Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. Am J Surg Pathol. 2005, 29: 734-746. 10.1097\/01.pas.0000157295.93914.3b.","journal-title":"Am J Surg Pathol"},{"key":"1497_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ydbio.2006.08.028","volume":"302","author":"B Zhang","year":"2007","unstructured":"Zhang B, Pan X, Cobb GP, Anderson TA: microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007, 302: 1-12. 10.1016\/j.ydbio.2006.08.028.","journal-title":"Dev Biol"},{"key":"1497_CR9","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1126\/science.1064921","volume":"294","author":"M Lagos-Quintana","year":"2001","unstructured":"Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T: Identification of novel genes coding for small expressed RNAs. Science. 2001, 294: 853-858. 10.1126\/science.1064921.","journal-title":"Science"},{"key":"1497_CR10","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1126\/science.1065062","volume":"294","author":"NC Lau","year":"2001","unstructured":"Lau NC, Lim LP, Weinstein EG, Bartel DP: An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001, 294: 858-862. 10.1126\/science.1065062.","journal-title":"Science"},{"key":"1497_CR11","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1126\/science.1065329","volume":"294","author":"RC Lee","year":"2001","unstructured":"Lee RC, Ambros V: An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001, 294: 862-864. 10.1126\/science.1065329.","journal-title":"Science"},{"key":"1497_CR12","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/0092-8674(93)90529-Y","volume":"75","author":"RC Lee","year":"1993","unstructured":"Lee RC, Feinbaum RL, Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993, 75: 843-854. 10.1016\/0092-8674(93)90529-Y.","journal-title":"Cell"},{"key":"1497_CR13","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1073\/pnas.0510565103","volume":"103","author":"S Volinia","year":"2006","unstructured":"Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006, 103: 2257-2261. 10.1073\/pnas.0510565103.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1497_CR14","doi-asserted-by":"publisher","first-page":"7065","DOI":"10.1158\/0008-5472.CAN-05-1783","volume":"65","author":"MV Iorio","year":"2005","unstructured":"Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al: MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005, 65: 7065-7070. 10.1158\/0008-5472.CAN-05-1783.","journal-title":"Cancer Res"},{"key":"1497_CR15","doi-asserted-by":"publisher","first-page":"14328","DOI":"10.1074\/jbc.M611393200","volume":"282","author":"S Zhu","year":"2007","unstructured":"Zhu S, Si ML, Wu H, Mo YY: MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007, 282: 14328-14336. 10.1074\/jbc.M611393200.","journal-title":"J Biol Chem"},{"key":"1497_CR16","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1074\/jbc.M707224200","volume":"283","author":"LB Frankel","year":"2008","unstructured":"Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH: 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. 10.1074\/jbc.M707224200.","journal-title":"J Biol Chem"},{"key":"1497_CR17","doi-asserted-by":"publisher","first-page":"6029","DOI":"10.1158\/0008-5472.CAN-05-0137","volume":"65","author":"JA Chan","year":"2005","unstructured":"Chan JA, Krichevsky AM, Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005, 65: 6029-6033. 10.1158\/0008-5472.CAN-05-0137.","journal-title":"Cancer Res"},{"key":"1497_CR18","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1053\/j.gastro.2007.05.022","volume":"133","author":"F Meng","year":"2007","unstructured":"Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007, 133: 647-658. 10.1053\/j.gastro.2007.05.022.","journal-title":"Gastroenterology"},{"key":"1497_CR19","volume-title":"Preneoplasia of the Breast: A New Conceptual Approach to Proliferative Breast Disease","author":"W Boecker","year":"2006","unstructured":"Boecker W: Preneoplasia of the Breast: A New Conceptual Approach to Proliferative Breast Disease. 2006, Munich: Elsevier GmbH"},{"key":"1497_CR20","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1159\/000086981","volume":"68","author":"S Tsutsui","year":"2005","unstructured":"Tsutsui S, Inoue H, Yasuda K, Suzuki K, Higashi H, Era S, et al: Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology. 2005, 68: 398-404. 10.1159\/000086981.","journal-title":"Oncology"},{"key":"1497_CR21","doi-asserted-by":"publisher","first-page":"6194","DOI":"10.1038\/sj.onc.1206719","volume":"22","author":"GN Raval","year":"2003","unstructured":"Raval GN, Bharadwaj S, Levine EA, Willingham MC, Geary RL, Kute T, et al: Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors. Oncogene. 2003, 22: 6194-6203. 10.1038\/sj.onc.1206719.","journal-title":"Oncogene"},{"key":"1497_CR22","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1002\/cncr.22983","volume":"110","author":"G Mudduluru","year":"2007","unstructured":"Mudduluru G, Medved F, Grobholz R, Jost C, Gruber A, Leupold JH, et al: Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer. Cancer. 2007, 110: 1697-1707. 10.1002\/cncr.22983.","journal-title":"Cancer"},{"key":"1497_CR23","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1002\/path.1929","volume":"208","author":"PC Verhagen","year":"2006","unstructured":"Verhagen PC, van Duijn PW, Hermans KG, Looijenga LH, van Gurp RJ, Stoop H, et al: The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion. J Pathol. 2006, 208: 699-707. 10.1002\/path.1929.","journal-title":"J Pathol"},{"key":"1497_CR24","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1093\/nar\/gkp040","volume":"37","author":"T Haraguchi","year":"2009","unstructured":"Haraguchi T, Ozaki Y, Iba H: Vectors expressing efficient RNA decoys achieve the long-term suppression of specific microRNA activity in mammalian cells. Nucleic Acids Res. 2009, 37: e43-10.1093\/nar\/gkp040.","journal-title":"Nucleic Acids Res"},{"key":"1497_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.virol.2009.01.036","volume":"386","author":"B Akgul","year":"2009","unstructured":"Akgul B, Zigrino P, Frith D, Hanrahan S, Storey A: Proteomic analysis reveals the actin cytoskeleton as cellular target for the human papillomavirus type 8. Virology. 2009, 386: 1-5. 10.1016\/j.virol.2009.01.036.","journal-title":"Virology"},{"key":"1497_CR26","doi-asserted-by":"publisher","first-page":"11612","DOI":"10.1158\/0008-5472.CAN-07-5019","volume":"67","author":"LF Sempere","year":"2007","unstructured":"Sempere LF, Christensen M, Silahtaroglu A, Bak M, Heath CV, Schwartz G, et al: Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res. 2007, 67: 11612-11620. 10.1158\/0008-5472.CAN-07-5019.","journal-title":"Cancer Res"},{"key":"1497_CR27","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/cr.2008.24","volume":"18","author":"S Zhu","year":"2008","unstructured":"Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY: MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008, 18: 350-359. 10.1038\/cr.2008.24.","journal-title":"Cell Res"},{"key":"1497_CR28","doi-asserted-by":"publisher","first-page":"4373","DOI":"10.1038\/onc.2008.72","volume":"27","author":"Z Lu","year":"2008","unstructured":"Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH, et al: MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 2008, 27: 4373-4379. 10.1038\/onc.2008.72.","journal-title":"Oncogene"},{"key":"1497_CR29","first-page":"M21","volume":"1470","author":"F Vazquez","year":"2000","unstructured":"Vazquez F, Sellers WR: The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta. 2000, 1470: M21-M35.","journal-title":"Biochim Biophys Acta"},{"key":"1497_CR30","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.biopha.2007.08.015","volume":"61","author":"L Zhu","year":"2007","unstructured":"Zhu L, Loo WT, Louis WC: PTEN and VEGF: possible predictors for sentinel lymph node micro-metastasis in breast cancer. Biomed Pharmacother. 2007, 61: 558-561. 10.1016\/j.biopha.2007.08.015.","journal-title":"Biomed Pharmacother"},{"key":"1497_CR31","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/modpathol.3800525","volume":"19","author":"S Bose","year":"2006","unstructured":"Bose S, Chandran S, Mirocha JM, Bose N: The Akt pathway in human breast cancer: a tissue-array-based analysis. Mod Pathol. 2006, 19: 238-245. 10.1038\/modpathol.3800525.","journal-title":"Mod Pathol"},{"key":"1497_CR32","first-page":"1387","volume":"18","author":"YH Wen","year":"2007","unstructured":"Wen YH, Shi X, Chiriboga L, Matsahashi S, Yee H, Afonja O: Alterations in the expression of PDCD4 in ductal carcinoma of the breast. Oncol Rep. 2007, 18: 1387-1393.","journal-title":"Oncol Rep"},{"key":"1497_CR33","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0304-3835(02)00119-2","volume":"183","author":"S Bharadwaj","year":"2002","unstructured":"Bharadwaj S, Prasad GL: Tropomyosin-1, a novel suppressor of cellular transformation is downregulated by promoter methylation in cancer cells. Cancer Lett. 2002, 183: 205-213. 10.1016\/S0304-3835(02)00119-2.","journal-title":"Cancer Lett"},{"key":"1497_CR34","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/onc.2008.370","volume":"28","author":"F Talotta","year":"2009","unstructured":"Talotta F, Cimmino A, Matarazzo MR, Casalino L, De Vita G, D'Esposito M, et al: An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene. 2009, 28: 73-84. 10.1038\/onc.2008.370.","journal-title":"Oncogene"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-9-163.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1471-2407-9-163\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-9-163","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-9-163.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T02:19:42Z","timestamp":1630462782000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/1471-2407-9-163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,28]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["1497"],"URL":"https:\/\/doi.org\/10.1186\/1471-2407-9-163","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,28]]},"assertion":[{"value":"12 November 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 May 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"163"}}