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dc.contributor.authorGregory, Kelly J.
dc.contributor.authorCrisi, Giovanna M.
dc.contributor.authorBentley, Brooke A.
dc.contributor.authorMakari-Judson, Grace
dc.contributor.authorMason, Holly S.
dc.contributor.authorYu, Jun
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorSimin, Karl J.
dc.contributor.authorJohnson, Jacob P. S.
dc.contributor.authorKhan, Ashraf
dc.contributor.authorSchneider, Sallie S.
dc.contributor.authorJerry, D. Joseph
dc.date2022-08-11T08:09:53.000
dc.date.accessioned2022-08-23T16:47:27Z
dc.date.available2022-08-23T16:47:27Z
dc.date.issued2019-06-27
dc.date.submitted2019-07-18
dc.identifier.citation<p>Breast Cancer Res. 2019 Jun 27;21(1):76. doi: 10.1186/s13058-019-1157-5. <a href="https://doi.org/10.1186/s13058-019-1157-5">Link to article on publisher's site</a></p>
dc.identifier.issn1465-5411 (Linking)
dc.identifier.doi10.1186/s13058-019-1157-5
dc.identifier.pmid31248446
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41083
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractBACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERalpha+) and represent risk indicators and/or precursor lesions to low grade ERalpha+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERalpha, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31248446&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rights© The Author(s). 2019 Open Access: This 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.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAtypical hyperplasia
dc.subjectBreast
dc.subjectDuctal
dc.subjectGene expression profile
dc.subjectLobular
dc.subjectPremalignancy
dc.subjectSFRP1
dc.subjectCancer Biology
dc.subjectNeoplasms
dc.subjectPathological Conditions, Signs and Symptoms
dc.subjectSkin and Connective Tissue Diseases
dc.titleGene expression signature of atypical breast hyperplasia and regulation by SFRP1
dc.typeJournal Article
dc.source.journaltitleBreast cancer research : BCR
dc.source.volume21
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4888&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3873
dc.identifier.contextkey14951167
refterms.dateFOA2022-08-23T16:47:28Z
html.description.abstract<p>BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERalpha+) and represent risk indicators and/or precursor lesions to low grade ERalpha+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation.</p> <p>METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues.</p> <p>RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERalpha, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels.</p> <p>CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.</p>
dc.identifier.submissionpathoapubs/3873
dc.contributor.departmentBaystate Medical Center
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Molecular, Cell, and Cancer Biology
dc.source.pages76


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© The Author(s). 2019 Open Access: This 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.
Except where otherwise noted, this item's license is described as © The Author(s). 2019 Open Access: This 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.