A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance
Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling a...
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| Veröffentlicht in: | Oncogene 2021-02, Vol.40 (7), p.1300-1317 |
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| creator | Al-Akhrass, Hussein Conway, James R. W. Poulsen, Annemarie Svane Aavild Paatero, Ilkka Kaivola, Jasmin Padzik, Artur Andersen, Olav M. Ivaska, Johanna |
| description | Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA;
SORL1
). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model. |
| doi_str_mv | 10.1038/s41388-020-01604-5 |
| format | Article |
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SORL1
). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-01604-5</identifier><identifier>PMID: 33420373</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/95 ; 14/19 ; 631/67/1347 ; 631/80/86/2368 ; 64/116 ; 82/103 ; 96/109 ; 96/35 ; Animals ; Apoptosis ; Biochemistry & Molecular Biology ; Brain - drug effects ; Brain - metabolism ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Care and treatment ; Cell Biology ; Cell proliferation ; Cell Proliferation - drug effects ; Cell surface ; Development and progression ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Epidermal growth factor ; ErbB-2 protein ; Female ; Gene expression ; Genetic aspects ; Genetics & Heredity ; Health aspects ; Heregulin ; Heterografts ; Human Genetics ; Humans ; Internal Medicine ; Kinases ; LDL-Receptor Related Proteins - genetics ; Life Sciences & Biomedicine ; Lysosomes ; MAP kinase ; Medicine ; Medicine & Public Health ; Membrane Transport Proteins - genetics ; Metastases ; Mice ; Neuregulin-1 - pharmacology ; Oncology ; Protein-tyrosine kinase ; Protein-tyrosine kinase receptors ; rab4 GTP-Binding Proteins - genetics ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-3 - genetics ; Science & Technology ; Spheroids ; Spheroids, Cellular - drug effects ; Spheroids, Cellular - metabolism ; Transcription ; Xenografts ; Zebrafish</subject><ispartof>Oncogene, 2021-02, Vol.40 (7), p.1300-1317</ispartof><rights>The Author(s) 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s) 2021. This work is published under http://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>19</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000607346000002</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c541t-58790d45faf9c696510775c2ece5aa5c2a7fdde654bdc5d684b7045300802a363</citedby><cites>FETCH-LOGICAL-c541t-58790d45faf9c696510775c2ece5aa5c2a7fdde654bdc5d684b7045300802a363</cites><orcidid>0000-0001-5926-2396 ; 0000-0002-9630-3000 ; 0000-0002-6295-6556 ; 0000-0002-1437-1828</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930,39263</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33420373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Al-Akhrass, Hussein</creatorcontrib><creatorcontrib>Conway, James R. W.</creatorcontrib><creatorcontrib>Poulsen, Annemarie Svane Aavild</creatorcontrib><creatorcontrib>Paatero, Ilkka</creatorcontrib><creatorcontrib>Kaivola, Jasmin</creatorcontrib><creatorcontrib>Padzik, Artur</creatorcontrib><creatorcontrib>Andersen, Olav M.</creatorcontrib><creatorcontrib>Ivaska, Johanna</creatorcontrib><title>A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>ONCOGENE</addtitle><addtitle>Oncogene</addtitle><description>Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA;
SORL1
). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.</description><subject>13/95</subject><subject>14/19</subject><subject>631/67/1347</subject><subject>631/80/86/2368</subject><subject>64/116</subject><subject>82/103</subject><subject>96/109</subject><subject>96/35</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry & Molecular Biology</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell surface</subject><subject>Development and progression</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Epidermal growth factor</subject><subject>ErbB-2 protein</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetics & Heredity</subject><subject>Health aspects</subject><subject>Heregulin</subject><subject>Heterografts</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>LDL-Receptor Related Proteins - genetics</subject><subject>Life Sciences & Biomedicine</subject><subject>Lysosomes</subject><subject>MAP kinase</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Metastases</subject><subject>Mice</subject><subject>Neuregulin-1 - pharmacology</subject><subject>Oncology</subject><subject>Protein-tyrosine kinase</subject><subject>Protein-tyrosine kinase receptors</subject><subject>rab4 GTP-Binding Proteins - genetics</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-3 - genetics</subject><subject>Science & Technology</subject><subject>Spheroids</subject><subject>Spheroids, Cellular - drug effects</subject><subject>Spheroids, Cellular - metabolism</subject><subject>Transcription</subject><subject>Xenografts</subject><subject>Zebrafish</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-AS9kwBtBpp58z9wIy1KtsCD4cR0yyZltymyyJjMu_nuz3bq2ImJykXDyvCcnJ29VPSdwToC1bzInrG0boNAAkcAb8aA6JVzJRoiOP6xOoRPQdJTRk-pJztcAoDqgj6sTxjgFpthpZRb1gOiaIaadSa4eY9zWPU47xFB_jmm1qE1w9eXFJ1Y7nDBtfMBcX2HC9Tz6UCfM2xgy3mABk5l88P0-7PNkgsWn1aPBjBmf3a5n1dd3F1-Wl83q4_sPy8WqsYKTqRFtqc1xMZihs7KTgoBSwlK0KIwpG6MG51AK3jsrnGx5r4ALBtACNUyys-rtIe927jfoLIYpmVFvk9-Y9ENH4_X9k-Cv9Dp-16otLeKqJHh1myDFbzPmSW98tjiOJmCcs6als0IC7dqCvvwDvY5zCuV5heqg7Qhld6i1GVH7MMRyr90n1QsphCKcCFao879QZTrceBsDDr7E7wnoQWBTzDnhcHwjAb03hj4YQxdj6BtjaFFEL-525yj55YQCtAdgh30csvVY_u6IFetIUIxL2A-69FP55xiWcQ5Tkb7-f2mh2YHOhQhrTL9794_6fwL6FuLQ</recordid><startdate>20210218</startdate><enddate>20210218</enddate><creator>Al-Akhrass, Hussein</creator><creator>Conway, James R. 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W.</au><au>Poulsen, Annemarie Svane Aavild</au><au>Paatero, Ilkka</au><au>Kaivola, Jasmin</au><au>Padzik, Artur</au><au>Andersen, Olav M.</au><au>Ivaska, Johanna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><stitle>ONCOGENE</stitle><addtitle>Oncogene</addtitle><date>2021-02-18</date><risdate>2021</risdate><volume>40</volume><issue>7</issue><spage>1300</spage><epage>1317</epage><pages>1300-1317</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA;
SORL1
). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33420373</pmid><doi>10.1038/s41388-020-01604-5</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-5926-2396</orcidid><orcidid>https://orcid.org/0000-0002-9630-3000</orcidid><orcidid>https://orcid.org/0000-0002-6295-6556</orcidid><orcidid>https://orcid.org/0000-0002-1437-1828</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Oncogene, 2021-02, Vol.40 (7), p.1300-1317 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_gale_infotracmisc_A655714153 |
| source | MEDLINE; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Alma/SFX Local Collection |
| subjects | 13/95 14/19 631/67/1347 631/80/86/2368 64/116 82/103 96/109 96/35 Animals Apoptosis Biochemistry & Molecular Biology Brain - drug effects Brain - metabolism Breast cancer Breast Neoplasms - genetics Breast Neoplasms - pathology Care and treatment Cell Biology Cell proliferation Cell Proliferation - drug effects Cell surface Development and progression Drug resistance Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Epidermal growth factor ErbB-2 protein Female Gene expression Genetic aspects Genetics & Heredity Health aspects Heregulin Heterografts Human Genetics Humans Internal Medicine Kinases LDL-Receptor Related Proteins - genetics Life Sciences & Biomedicine Lysosomes MAP kinase Medicine Medicine & Public Health Membrane Transport Proteins - genetics Metastases Mice Neuregulin-1 - pharmacology Oncology Protein-tyrosine kinase Protein-tyrosine kinase receptors rab4 GTP-Binding Proteins - genetics Receptor, ErbB-2 - genetics Receptor, ErbB-3 - genetics Science & Technology Spheroids Spheroids, Cellular - drug effects Spheroids, Cellular - metabolism Transcription Xenografts Zebrafish |
| title | A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T01%3A59%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20feed-forward%20loop%20between%20SorLA%20and%20HER3%20determines%20heregulin%20response%20and%20neratinib%20resistance&rft.jtitle=Oncogene&rft.au=Al-Akhrass,%20Hussein&rft.date=2021-02-18&rft.volume=40&rft.issue=7&rft.spage=1300&rft.epage=1317&rft.pages=1300-1317&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-020-01604-5&rft_dat=%3Cgale_webof%3EA655714153%3C/gale_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2490891238&rft_id=info:pmid/33420373&rft_galeid=A655714153&rfr_iscdi=true |