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dc.contributor.authorElsarraj, Hanan S.
dc.contributor.authorHong, Yan
dc.contributor.authorValdez, Kelli E.
dc.contributor.authorMichaels, Whitney
dc.contributor.authorHook, Marcus
dc.contributor.authorSmith, William P.
dc.contributor.authorChien, Jeremy
dc.contributor.authorHerschkowitz, Jason I.
dc.contributor.authorTroester, Melissa A.
dc.contributor.authorBeck, Moriah R.
dc.contributor.authorInciardi, Marc
dc.contributor.authorGatewood, Jason
dc.contributor.authorMay, Lisa
dc.contributor.authorCusick, Therese
dc.contributor.authorMcGinness, Marilee
dc.contributor.authorRicci, Lawrence
dc.contributor.authorFan, Fang
dc.contributor.authorTawfik, Ossama
dc.contributor.authorMarks, Jeffrey R.
dc.contributor.authorKnapp, Jennifer R.
dc.contributor.authorYeh, Hung-Wen
dc.contributor.authorThomas, Patricia
dc.contributor.authorCarrasco, D. R.
dc.contributor.authorFields, Timothy A.
dc.contributor.authorGodwin, Andrew K.
dc.contributor.authorBehbod, Fariba
dc.date.accessioned2015-10-28T20:33:18Z
dc.date.available2015-10-28T20:33:18Z
dc.date.issued2015-09-17
dc.identifier.citationElsarraj, Hanan S.; Hong, Yan; Valdez, Kelli E.; Michaels, Whitney; Hook, Marcus; Smith, William P.; Chien, Jeremy; Herschkowitz, Jason I.; Troester, Melissa A.; Beck, Moriah R.; Inciardi, Marc; Gatewood, Jason; May, Lisa; Cusick, Therese; McGinness, Marilee; Ricci, Lawrence; Fan, Fang; Tawfik, Ossama; Marks, Jeffrey R.; Knapp, Jennifer R.; Yeh, Hung-Wen; Thomas, Patricia; Carrasco, D. R.; Fields, Timothy A.; Godwin, Andrew K.; Behbod, Fariba. 2015. Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion. Breast Cancer Research, vol. 17:article 128en_US
dc.identifier.issn1465-542X
dc.identifier.otherWOS:000361283900002
dc.identifier.urihttp://dx.doi.org/10.1186/s13058-015-0630-z
dc.identifier.urihttp://hdl.handle.net/10057/11559
dc.description© 2015 Elsarraj et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
dc.description.abstractIntroduction: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated beta-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. Methods: Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. Results: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. Conclusion: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.en_US
dc.description.sponsorshipThis study was supported in part by grants from 2014 Breast Cancer Research Foundation-AACR, NIH/NCI 1R21CA185460-01 and Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health P20 GM103418 (FB); by the NCI Early Detection Research Network (U01 CA084955 to JRM and U01CA113916 to AKG), and by the Komen Foundation (BCTR0603000) to TAF. The authors also acknowledge support from The University of Kansas Cancer Center (P30 CA168524). AKG was funded by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. HE was supported by the Libyan-North American Scholarship program. We would like to acknowledge the University of Kansas Cancer Center Biospecimen Repository Core Facility staff for helping obtain human specimens. We thank the Kansas University Medical Center-Genomics Core for generating the array and sequencing data sets. The Genomics Core is supported by the Kansas University-School of Medicine and the Smith Intellectual and Developmental Disabilities Research Center (HD02528). Data analysis is supported by the K-INBRE Bioinformatics Core, NIH grant number P20 RR016475.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Central Ltden_US
dc.relation.ispartofseriesBreast Cancer Research;v.17:article128
dc.subjectWNT Signaling pathwayen_US
dc.subjectCandidate genesen_US
dc.subjectRNA-SEQen_US
dc.subjectActivationen_US
dc.subjectMarkersen_US
dc.subjectComplexen_US
dc.subjectTargeten_US
dc.subjectColonen_US
dc.subjectNotchen_US
dc.subjectDCISen_US
dc.titleExpression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasionen_US
dc.typeArticleen_US
dc.rights.holder© 2015 BioMed Central Ltden_US


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