{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:23:30Z","timestamp":1790400210765,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,2,16]],"date-time":"2009-02-16T00:00:00Z","timestamp":1234742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2009,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Invasive lobular carcinoma (ILC) of the breast is believed to develop from\n                    <jats:italic>in situ<\/jats:italic>\n                    lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma\n                    <jats:italic>in situ<\/jats:italic>\n                    (LCIS). Down\u2010regulation of the cell\u2013cell adhesion protein E\u2010cadherin is a defining feature of lobular breast cancer (LBC) and already occurs in ALH and LCIS. Apart from mutational mechanisms, epigenetic silencing of the E\u2010cadherin gene (\n                    <jats:italic>CDH1<\/jats:italic>\n                    ) is thought to be involved in E\u2010cadherin down\u2010regulation and has been observed at a high frequency in ILC. Whether\n                    <jats:italic>CDH1<\/jats:italic>\n                    promoter methylation is already present in\n                    <jats:italic>in situ<\/jats:italic>\n                    lesions and thus contributes to the initiation of LBC is not established. We thus examined microdissected archived tissue from 20 LBCs by methylation\u2010specific PCR to determine the\n                    <jats:italic>CDH1<\/jats:italic>\n                    methylation status of lobular lesions. Nineteen of the 20 LBCs had a hypermethylated\n                    <jats:italic>CDH1<\/jats:italic>\n                    promoter, including 13\/14 ILCs and 13\/13 ALHs or LCIS. Bisulphite sequencing indicated that methylation was complete within the investigated promoter fragment. Intriguingly,\n                    <jats:italic>CDH1<\/jats:italic>\n                    methylation was likewise present in 8\/8 adjacent non\u2010neoplastic epithelia, but not in 6\/6 mammary epithelia from healthy subjects. E\u2010cadherin protein and mRNA were down\u2010regulated in\n                    <jats:italic>in situ<\/jats:italic>\n                    lesions relative to adjacent epithelia. Together, these results indicate that\n                    <jats:italic>CDH1<\/jats:italic>\n                    promoter methylation occurs in LBC prior to E\u2010cadherin down\u2010regulation and neoplastic formation. We thus propose that epigenetic silencing represents the first of the two hits required to silence both\n                    <jats:italic>CDH1<\/jats:italic>\n                    alleles for LBC to develop. Because promoter methylation is in principle reversible, our findings suggest that chemoprevention of LBC by epigenetic drugs should be feasible. Furthermore, the presence of\n                    <jats:italic>CDH1<\/jats:italic>\n                    methylation in pre\u2010neoplastic epithelia suggests the existence of mammary regions with increased disease susceptibility, providing an explanation for the often multifocal presentation of LBC. Copyright \u00a9 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.\n                  <\/jats:p>","DOI":"10.1002\/path.2541","type":"journal-article","created":{"date-parts":[[2009,2,16]],"date-time":"2009-02-16T09:08:37Z","timestamp":1234775317000},"page":"265-272","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Epigenetic silencing in non\u2010neoplastic epithelia identifies E\u2010cadherin (\n                    <i>CDH1<\/i>\n                    ) as a target for chemoprevention of lobular neoplasia"],"prefix":"10.1002","volume":"218","author":[{"given":"Donghui","family":"Zou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010Seung","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Weeks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parry","family":"Guilford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bostjan","family":"Humar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,3,17]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.11.1421"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1785"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2007.02891.x"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800362"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11197"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1997.523"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.09.013"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/1897-4287-5-4-183"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2007.051268"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2457"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-6-48"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.041"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.1208"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/07357900701719234"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3021"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.35.22322"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-03-0320"},{"key":"e_1_2_7_19_2","first-page":"1179","article-title":"Expression of putative anticancer targets in familial adenomatous polyposis and its association with the APC mutation status","volume":"19","author":"Humar B","year":"2001","journal-title":"Int J Oncol"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207439"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-004-4493-8"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2559.2001.01252.x"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004280050469"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2007.40.2.142"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0467"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64195-8"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-07-2582"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-0407"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.166.11.1"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.2541","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.2541","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T17:30:34Z","timestamp":1761067834000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.2541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,17]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2009,6]]}},"alternative-id":["10.1002\/path.2541"],"URL":"https:\/\/doi.org\/10.1002\/path.2541","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,17]]},"assertion":[{"value":"2009-01-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-02-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-03-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}