E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements
Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell...
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| Veröffentlicht in: | Modern pathology 2020-12, Vol.33 (12), p.2483-2498 |
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| creator | Christgen, Matthias Bartels, Stephan van Luttikhuizen, Jana L. Bublitz, Janin Rieger, Luisa U. Christgen, Henriette Stark, Helge Sander, Bjoern Lehmann, Ulrich Steinemann, Doris Derksen, Patrick W.B. Kreipe, Hans |
| description | Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements. |
| doi_str_mv | 10.1038/s41379-020-0591-3 |
| format | Article |
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Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.</description><identifier>ISSN: 0893-3952</identifier><identifier>EISSN: 1530-0285</identifier><identifier>DOI: 10.1038/s41379-020-0591-3</identifier><identifier>PMID: 32572153</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>13/105 ; 14/1 ; 45/22 ; 45/23 ; 631/67/1347 ; 631/80/79 ; Adherens junctions ; Adult ; Aged ; Antigens, CD - analysis ; Antigens, CD - genetics ; Biomarkers, Tumor - analysis ; Biomarkers, Tumor - genetics ; Breast cancer ; Breast Neoplasms - chemistry ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cadherins - analysis ; Cadherins - genetics ; Carcinoma, Lobular - chemistry ; Carcinoma, Lobular - genetics ; Carcinoma, Lobular - pathology ; CDH1 gene ; Cell adhesion ; Cell adhesion & migration ; Chromosome deletion ; Copy number ; DNA Copy Number Variations ; DNA Mutational Analysis ; E-cadherin ; ErbB-2 protein ; Female ; Gene deletion ; Gene Dosage ; Gene Expression Regulation, Neoplastic ; Genomes ; Grills ; Heterozygosity ; Humans ; Immunohistochemistry ; Invasiveness ; Laboratory Medicine ; Life Sciences & Biomedicine ; Loss of Heterozygosity ; Mammary gland ; Medicine ; Medicine & Public Health ; Middle Aged ; Mutation ; N-Cadherin ; Next-generation sequencing ; Pathology ; RNA-Seq ; Science & Technology ; Tumor cells ; β-Catenin</subject><ispartof>Modern pathology, 2020-12, Vol.33 (12), p.2483-2498</ispartof><rights>2020 The Authors</rights><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>27</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000542079500005</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c522t-ac33cb7d4f6c292152e719d309a3f330547992aa78350149e48eeb1ff74acad23</citedby><cites>FETCH-LOGICAL-c522t-ac33cb7d4f6c292152e719d309a3f330547992aa78350149e48eeb1ff74acad23</cites><orcidid>0000-0002-8903-2345 ; 0000-0002-2668-8056 ; 0000-0003-0732-7762 ; 0000-0001-8495-2321</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2473251111?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,64385,64387,64389,72341</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32572153$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Christgen, Matthias</creatorcontrib><creatorcontrib>Bartels, Stephan</creatorcontrib><creatorcontrib>van Luttikhuizen, Jana L.</creatorcontrib><creatorcontrib>Bublitz, Janin</creatorcontrib><creatorcontrib>Rieger, Luisa U.</creatorcontrib><creatorcontrib>Christgen, Henriette</creatorcontrib><creatorcontrib>Stark, Helge</creatorcontrib><creatorcontrib>Sander, Bjoern</creatorcontrib><creatorcontrib>Lehmann, Ulrich</creatorcontrib><creatorcontrib>Steinemann, Doris</creatorcontrib><creatorcontrib>Derksen, Patrick W.B.</creatorcontrib><creatorcontrib>Kreipe, Hans</creatorcontrib><title>E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements</title><title>Modern pathology</title><addtitle>Mod Pathol</addtitle><addtitle>MODERN PATHOL</addtitle><addtitle>Mod Pathol</addtitle><description>Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.</description><subject>13/105</subject><subject>14/1</subject><subject>45/22</subject><subject>45/23</subject><subject>631/67/1347</subject><subject>631/80/79</subject><subject>Adherens junctions</subject><subject>Adult</subject><subject>Aged</subject><subject>Antigens, CD - analysis</subject><subject>Antigens, CD - genetics</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - chemistry</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cadherins - analysis</subject><subject>Cadherins - genetics</subject><subject>Carcinoma, Lobular - chemistry</subject><subject>Carcinoma, Lobular - genetics</subject><subject>Carcinoma, Lobular - pathology</subject><subject>CDH1 gene</subject><subject>Cell 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to P-cadherin switching in lobular breast cancer with tubular elements</title><author>Christgen, Matthias ; Bartels, Stephan ; van Luttikhuizen, Jana L. ; Bublitz, Janin ; Rieger, Luisa U. ; Christgen, Henriette ; Stark, Helge ; Sander, Bjoern ; Lehmann, Ulrich ; Steinemann, Doris ; Derksen, Patrick W.B. ; Kreipe, Hans</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-ac33cb7d4f6c292152e719d309a3f330547992aa78350149e48eeb1ff74acad23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/105</topic><topic>14/1</topic><topic>45/22</topic><topic>45/23</topic><topic>631/67/1347</topic><topic>631/80/79</topic><topic>Adherens junctions</topic><topic>Adult</topic><topic>Aged</topic><topic>Antigens, CD - analysis</topic><topic>Antigens, CD - genetics</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - chemistry</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Cadherins - analysis</topic><topic>Cadherins - genetics</topic><topic>Carcinoma, Lobular - chemistry</topic><topic>Carcinoma, Lobular - genetics</topic><topic>Carcinoma, Lobular - pathology</topic><topic>CDH1 gene</topic><topic>Cell adhesion</topic><topic>Cell adhesion & migration</topic><topic>Chromosome deletion</topic><topic>Copy number</topic><topic>DNA Copy Number Variations</topic><topic>DNA Mutational Analysis</topic><topic>E-cadherin</topic><topic>ErbB-2 protein</topic><topic>Female</topic><topic>Gene deletion</topic><topic>Gene Dosage</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genomes</topic><topic>Grills</topic><topic>Heterozygosity</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Invasiveness</topic><topic>Laboratory Medicine</topic><topic>Life Sciences & Biomedicine</topic><topic>Loss of Heterozygosity</topic><topic>Mammary gland</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>N-Cadherin</topic><topic>Next-generation sequencing</topic><topic>Pathology</topic><topic>RNA-Seq</topic><topic>Science & Technology</topic><topic>Tumor cells</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Christgen, Matthias</creatorcontrib><creatorcontrib>Bartels, Stephan</creatorcontrib><creatorcontrib>van Luttikhuizen, Jana L.</creatorcontrib><creatorcontrib>Bublitz, Janin</creatorcontrib><creatorcontrib>Rieger, Luisa U.</creatorcontrib><creatorcontrib>Christgen, Henriette</creatorcontrib><creatorcontrib>Stark, Helge</creatorcontrib><creatorcontrib>Sander, Bjoern</creatorcontrib><creatorcontrib>Lehmann, Ulrich</creatorcontrib><creatorcontrib>Steinemann, Doris</creatorcontrib><creatorcontrib>Derksen, Patrick 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Christgen, Matthias</au><au>Bartels, Stephan</au><au>van Luttikhuizen, Jana L.</au><au>Bublitz, Janin</au><au>Rieger, Luisa U.</au><au>Christgen, Henriette</au><au>Stark, Helge</au><au>Sander, Bjoern</au><au>Lehmann, Ulrich</au><au>Steinemann, Doris</au><au>Derksen, Patrick W.B.</au><au>Kreipe, Hans</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements</atitle><jtitle>Modern pathology</jtitle><stitle>Mod Pathol</stitle><stitle>MODERN PATHOL</stitle><addtitle>Mod Pathol</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>33</volume><issue>12</issue><spage>2483</spage><epage>2498</epage><pages>2483-2498</pages><issn>0893-3952</issn><eissn>1530-0285</eissn><abstract>Loss of E-cadherin expression due to mutation of the CDH1 gene is a characteristic feature of invasive lobular breast cancer (ILBC). Beta-catenin, which binds to the cytoplasmic domain of E-cadherin, is simultaneously downregulated, reflecting disassembly of adherens junctions (AJs) and loss of cell adhesion. E-cadherin to P-cadherin expression switching can rescue AJs and cell adhesion. However, P-cadherin has not been implicated in ILBC, so far. We aimed to characterize 13 ILBCs with exceptional histomorphology, which we termed ILBCs with tubular elements. The CDH1 mutational status was determined by next generation sequencing and whole-genome copy number (CN) profiling. Expression of cadherins was assessed by immunohistochemistry. ILBCs with tubular elements were ER-positive (13/13) and HER2-negative (13/13) and harbored deleterious CDH1 mutations (11/13) accompanied by loss of heterozygosity due to deletion of chromosome 16q22.1 (9/11). E-cadherin expression was lost or reduced in noncohesive tumor cells and in admixed tubular elements (13/13). Beta-catenin expression was lost in noncohesive tumor cells, but was retained in tubular elements (11/13), indicating focal rescue of AJ formation. N-cadherin and R-cadherin were always negative (0/13). Strikingly, P-cadherin was commonly positive (12/13) and immunoreactivity was accentuated in tubular elements. Adjacent lobular carcinoma in situ (LCIS) was always P-cadherin-negative (0/7). In a reference cohort of LCIS specimens, P-cadherin was constantly not expressed (0/25). In a reference cohort of invasive mammary carcinomas, P-cadherin-positive cases (36/268, 13%) were associated with triple-negative nonlobular breast cancer (P < 0.001). Compared with ILBCs from the reference cohort, P-cadherin expression was more common in ILBCs with tubular elements (12/13 versus 7/84, P < 0.001). In summary, E-cadherin to P-cadherin switching occurs in a subset of ILBCs. P-cadherin is the molecular determinant of a mixed-appearing histomorphology in ILBCs with tubular elements.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>32572153</pmid><doi>10.1038/s41379-020-0591-3</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-8903-2345</orcidid><orcidid>https://orcid.org/0000-0002-2668-8056</orcidid><orcidid>https://orcid.org/0000-0003-0732-7762</orcidid><orcidid>https://orcid.org/0000-0001-8495-2321</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0893-3952 |
| ispartof | Modern pathology, 2020-12, Vol.33 (12), p.2483-2498 |
| issn | 0893-3952 1530-0285 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7685979 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | 13/105 14/1 45/22 45/23 631/67/1347 631/80/79 Adherens junctions Adult Aged Antigens, CD - analysis Antigens, CD - genetics Biomarkers, Tumor - analysis Biomarkers, Tumor - genetics Breast cancer Breast Neoplasms - chemistry Breast Neoplasms - genetics Breast Neoplasms - pathology Cadherins - analysis Cadherins - genetics Carcinoma, Lobular - chemistry Carcinoma, Lobular - genetics Carcinoma, Lobular - pathology CDH1 gene Cell adhesion Cell adhesion & migration Chromosome deletion Copy number DNA Copy Number Variations DNA Mutational Analysis E-cadherin ErbB-2 protein Female Gene deletion Gene Dosage Gene Expression Regulation, Neoplastic Genomes Grills Heterozygosity Humans Immunohistochemistry Invasiveness Laboratory Medicine Life Sciences & Biomedicine Loss of Heterozygosity Mammary gland Medicine Medicine & Public Health Middle Aged Mutation N-Cadherin Next-generation sequencing Pathology RNA-Seq Science & Technology Tumor cells β-Catenin |
| title | E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T03%3A23%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=E-cadherin%20to%20P-cadherin%20switching%20in%20lobular%20breast%20cancer%20with%20tubular%20elements&rft.jtitle=Modern%20pathology&rft.au=Christgen,%20Matthias&rft.date=2020-12-01&rft.volume=33&rft.issue=12&rft.spage=2483&rft.epage=2498&rft.pages=2483-2498&rft.issn=0893-3952&rft.eissn=1530-0285&rft_id=info:doi/10.1038/s41379-020-0591-3&rft_dat=%3Cproquest_webof%3E2416273946%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2473251111&rft_id=info:pmid/32572153&rft_els_id=S0893395222004197&rfr_iscdi=true |