{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:32:46Z","timestamp":1789565566530,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T00:00:00Z","timestamp":1584576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA016672"],"award-info":[{"award-number":["P30CA016672"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.<\/jats:p>","DOI":"10.3390\/cancers12030722","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T10:01:35Z","timestamp":1584612095000},"page":"722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Integrative Analyses of Multilevel Omics Reveal Preneoplastic Breast to Possess a Molecular Landscape That is Globally Shared with Invasive Basal-Like Breast Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Zhenlin","family":"Ju","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4234-0241","authenticated-orcid":false,"given":"Anjana","family":"Bhardwaj","sequence":"additional","affiliation":[{"name":"Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6784-0755","authenticated-orcid":false,"given":"Matthew","family":"Embury","sequence":"additional","affiliation":[{"name":"Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preethi","family":"Gunaratne","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Bedrosian","sequence":"additional","affiliation":[{"name":"Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/bcr311","article-title":"Mutations in normal breast tissue and breast tumours","volume":"3","author":"Tomlinson","year":"2001","journal-title":"Breast Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1126\/science.274.5295.2057","article-title":"Loss of heterozygosity in normal tissue adjacent to breast carcinomas","volume":"274","author":"Deng","year":"1996","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/ijc.23267","article-title":"Gene expression abnormalities in histologically normal breast epithelium of breast cancer patients","volume":"122","author":"Tripathi","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1126\/science.aab4082","article-title":"Somatic mutation in cancer and normal cells","volume":"349","author":"Martincorena","year":"2015","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1126\/science.aaa6806","article-title":"Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin","volume":"348","author":"Martincorena","year":"2015","journal-title":"Science"},{"key":"ref_6","first-page":"6075","article-title":"Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10","volume":"50","author":"Soule","year":"1990","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1242\/jcs.99.2.453","article-title":"Morphological expression of cell transformation induced by c-Ha-ras oncogene in human breast epithelial cells","volume":"99","author":"Russo","year":"1991","journal-title":"J. Cell Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1023\/A:1009577811584","article-title":"Xenograft models of premalignant breast disease","volume":"5","author":"Miller","year":"2000","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1023\/A:1006461422273","article-title":"Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells","volume":"65","author":"Santner","year":"2001","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1158\/0008-5472.CAN-04-0637","article-title":"Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival","volume":"64","author":"Takamizawa","year":"2004","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1155006","DOI":"10.1080\/23723556.2016.1155006","article-title":"The paradox of dicer in cancer","volume":"3","author":"Swahari","year":"2016","journal-title":"Mol. Cell Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1158\/0008-5472.CAN-06-3533","article-title":"Overexpression of Dicer in precursor lesions of lung adenocarcinoma","volume":"67","author":"Chiosea","year":"2007","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.bbrc.2003.12.002","article-title":"Defective RNA-mediated c-myc gene silencing pathway in Burkitt\u2019s lymphoma","volume":"313","author":"Kaul","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10549-012-2169-3","article-title":"Loss of Dicer expression is associated with breast cancer progression and recurrence","volume":"135","author":"Khoshnaw","year":"2012","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.humpath.2016.05.014","article-title":"Dicer expression in estrogen receptor-positive versus triple-negative breast cancer: An antibody comparison","volume":"56","author":"Spoelstra","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19645","DOI":"10.18632\/oncotarget.14902","article-title":"Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer","volume":"8","author":"Bhardwaj","year":"2017","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4365","DOI":"10.1093\/nar\/gkv328","article-title":"The many faces of Dicer: The complexity of the mechanisms regulating Dicer gene expression and enzyme activities","volume":"43","author":"Koralewska","year":"2015","journal-title":"Nucleic. Acids. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.molonc.2015.01.005","article-title":"MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase","volume":"9","author":"Pruikkonen","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s13058-018-1074-z","article-title":"The isomiR-140-3p-regulated mevalonic acid pathway as a potential target for prevention of triple negative breast cancer","volume":"20","author":"Bhardwaj","year":"2018","journal-title":"Breast Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.yexcr.2006.09.030","article-title":"Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor alpha signalling","volume":"313","author":"Taylor","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9431","DOI":"10.1093\/nar\/16.20.9431","article-title":"Isolation and characterization of a cDNA clone encoding the 19 kDa protein of signal recognition particle (SRP): Expression and binding to 7SL RNA","volume":"16","author":"Lingelbach","year":"1988","journal-title":"Nucleic. Acids. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/S1097-2765(01)00233-7","article-title":"Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA","volume":"7","author":"Huang","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/BF00219349","article-title":"PCR-assisted localization of the human SRPR gene","volume":"88","author":"Janin","year":"1992","journal-title":"Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"407","DOI":"10.7150\/jca.21394","article-title":"Role of miR-483 in digestive tract cancers: From basic research to clinical value","volume":"9","author":"Zhou","year":"2018","journal-title":"J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14134","DOI":"10.1073\/pnas.1005320107","article-title":"eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression","volume":"107","author":"Furic","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14879","DOI":"10.1073\/pnas.0803230105","article-title":"A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence","volume":"105","author":"Forman","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/gcc.20765","article-title":"Overexpression of dicer as a result of reduced let-7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells","volume":"49","author":"Jakymiw","year":"2010","journal-title":"Genes Chromosomes. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.cell.2010.05.017","article-title":"A MicroRNA targeting dicer for metastasis control","volume":"141","author":"Martello","year":"2010","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5974","DOI":"10.1073\/pnas.0931261100","article-title":"Gene expression profiles of human breast cancer progression","volume":"100","author":"Ma","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cai, Y., Nogales-Cadenas, R., Zhang, Q., Lin, J.R., Zhang, W., O\u2019Brien, K., Montagna, C., and Zhang, Z.D. (2017). Transcriptomic dynamics of breast cancer progression in the MMTV-PyMT mouse model. BMC Genomics, 18.","DOI":"10.1186\/s12864-017-3563-3"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.ygeno.2008.08.005","article-title":"Molecular signatures associated with transformation and progression to breast cancer in the isogenic MCF10 model","volume":"92","author":"Rhee","year":"2008","journal-title":"Genomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1007\/s11033-012-2277-5","article-title":"Genome-wide screen for aberrantly expressed miRNAs reveals miRNA profile signature in breast cancer","volume":"40","author":"Guo","year":"2013","journal-title":"Mol. Biol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s10549-008-0266-0","article-title":"Cyclin E deregulation is an early event in the development of breast cancer","volume":"115","author":"Shaye","year":"2009","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nature03702","article-title":"MicroRNA expression profiles classify human cancers","volume":"435","author":"Lu","year":"2005","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1126\/science.1149460","article-title":"Switching from repression to activation: microRNAs can up-regulate translation","volume":"318","author":"Vasudevan","year":"2007","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1158\/2159-8290.CD-17-0222","article-title":"Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition","volume":"7","author":"Huh","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/jnci\/92.14.1185a","article-title":"MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ","volume":"92","author":"Miller","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","article-title":"TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions","volume":"14","author":"Kim","year":"2013","journal-title":"Genome Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nprot.2012.016","article-title":"Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks","volume":"7","author":"Trapnell","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1038\/nsmb.2115","article-title":"Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs","volume":"18","author":"Garcia","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, S.Y., and Volsky, D.J. (2005). PAGE: Parametric analysis of gene set enrichment. BMC Bioinform., 6.","DOI":"10.1186\/1471-2105-6-144"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hartigan, J.A., and Wong, M.A. (1979). Algorithm AS 136: A K-Means Clustering Algorithm - LaBRI. J. R. Statist. Soc., 28.","DOI":"10.2307\/2346830"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/3\/722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:09:42Z","timestamp":1760173782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/3\/722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,19]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["cancers12030722"],"URL":"https:\/\/doi.org\/10.3390\/cancers12030722","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,19]]}}}