Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1
Abstract Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its charac...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202013180 |
| _version_ | 1797282027714641920 |
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| author | George Sflomos Laura Battista Patrick Aouad Fabio De Martino Valentina Scabia Athina Stravodimou Ayyakkannu Ayyanan Assia Ifticene‐Treboux RLS Philipp Bucher Maryse Fiche Giovanna Ambrosini Cathrin Brisken |
| author_facet | George Sflomos Laura Battista Patrick Aouad Fabio De Martino Valentina Scabia Athina Stravodimou Ayyakkannu Ayyanan Assia Ifticene‐Treboux RLS Philipp Bucher Maryse Fiche Giovanna Ambrosini Cathrin Brisken |
| author_sort | George Sflomos |
| collection | DOAJ |
| description | Abstract Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER+ HER2− tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC. |
| first_indexed | 2024-03-07T17:06:02Z |
| format | Article |
| id | doaj.art-8496cd22d6914407af3da1471f234dcb |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:06:02Z |
| publishDate | 2021-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-8496cd22d6914407af3da1471f234dcb2024-03-03T02:40:54ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-03-01133n/an/a10.15252/emmm.202013180Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1George Sflomos0Laura Battista1Patrick Aouad2Fabio De Martino3Valentina Scabia4Athina Stravodimou5Ayyakkannu Ayyanan6Assia Ifticene‐Treboux7RLS8Philipp Bucher9Maryse Fiche10Giovanna Ambrosini11Cathrin Brisken12ISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandLausanne University Hospital Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandLausanne University Hospital Lausanne SwitzerlandRéseau Lausannois du Sein (RLS) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandRéseau Lausannois du Sein (RLS) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandISREC ‐ Swiss Institute for Experimental Cancer Research School of Life Sciences Ecole Polytechnique Fédérale de Lausanne (EPFL) Lausanne SwitzerlandAbstract Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER+ HER2− tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC.https://doi.org/10.15252/emmm.202013180extracellular matrixlobular carcinomaLOXL1preclinical modelsxenografts |
| spellingShingle | George Sflomos Laura Battista Patrick Aouad Fabio De Martino Valentina Scabia Athina Stravodimou Ayyakkannu Ayyanan Assia Ifticene‐Treboux RLS Philipp Bucher Maryse Fiche Giovanna Ambrosini Cathrin Brisken Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 EMBO Molecular Medicine extracellular matrix lobular carcinoma LOXL1 preclinical models xenografts |
| title | Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 |
| title_full | Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 |
| title_fullStr | Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 |
| title_full_unstemmed | Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 |
| title_short | Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1 |
| title_sort | intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and loxl1 |
| topic | extracellular matrix lobular carcinoma LOXL1 preclinical models xenografts |
| url | https://doi.org/10.15252/emmm.202013180 |
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