HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/32046 http://dx.doi.org/10.1186/bcr2603 |
Resumo: | Introduction: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.Methods: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.Results: Most brain metastases were triple negative and basal-like. the brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. in particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.Conclusions: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. the need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules. |
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Da Silva, Leonard [UNIFESP]Simpson, Peter T.Smart, Chanel E.Cocciardi, SibylleWaddell, NicLane, AnnetteMorrison, Brian J.Vargas, Ana CristinaHealey, SueBeesley, JonathanPakkiri, PriaParry, SuzanneKurniawan, NyomanReid, LynneKeith, PatriciaFaria, PauloPereira, EmilioSkalova, AlenaBilous, MichaelBalleine, Rosemary L.Do, HongdoDobrovic, AlexanderFox, StephenFranco, Marcello [UNIFESP]Reynolds, BrentKhanna, Kum KumCummings, MargaretChenevix-Trench, GeorgiaLakhani, Sunil R.Univ QueenslandQueensland Inst Med ResUniversidade Federal de São Paulo (UNIFESP)Griffith UnivEijkman InstInst Nacl CancLab Salomao & ZoppiCharles Univ PragueUniv SydneyPeter MacCallum Canc CtrRoyal Brisbane & Womens Hosp2016-01-24T13:59:02Z2016-01-24T13:59:02Z2010-01-01Breast Cancer Research. London: Biomed Central Ltd, v. 12, n. 4, 13 p., 2010.1465-542Xhttp://repositorio.unifesp.br/handle/11600/32046http://dx.doi.org/10.1186/bcr2603WOS000285504100002.pdf10.1186/bcr2603WOS:000285504100002Introduction: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.Methods: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.Results: Most brain metastases were triple negative and basal-like. the brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. in particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.Conclusions: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. the need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.Ludwig Institute of Cancer ResearchNational Breast Cancer FoundationUniv Queensland, Clin Res Ctr, Brisbane, Qld 4029, AustraliaQueensland Inst Med Res, Brisbane, Qld 4006, AustraliaUniversidade Federal de São Paulo, EPM, Dept Anat Patol, BR-04024000 São Paulo, BrazilGriffith Univ, Brisbane, Qld 4011, AustraliaUniv Queensland, Ctr Magnet Resonance, Brisbane, Qld 4072, AustraliaEijkman Inst, Jakarta 10430, IndonesiaInst Nacl Canc, Dept Patol, BR-20230130 Rio de Janeiro, BrazilLab Salomao & Zoppi, Dept Patol, BR-04104000 São Paulo, BrazilCharles Univ Prague, Fac Med, Dept Pathol, Plzen 30605, Czech RepublicUniv Sydney, Inst Clin Pathol & Med Res, Sydney W Area Hlth Serv, Sydney, NSW 2145, AustraliaUniv Sydney, Westmead Millennium Inst, Sydney W Area Hlth Serv, Sydney, NSW 2145, AustraliaPeter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3002, AustraliaUniv Queensland, Queensland Brain Inst, Brisbane, Qld 4072, AustraliaRoyal Brisbane & Womens Hosp, Brisbane, Qld 4029, AustraliaUniversidade Federal de São Paulo, EPM, Dept Anat Patol, BR-04024000 São Paulo, BrazilWeb of Science13engBiomed Central LtdBreast Cancer ResearchHER3 and downstream pathways are involved in colonization of brain metastases from breast cancerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000285504100002.pdfapplication/pdf1836294${dspace.ui.url}/bitstream/11600/32046/1/WOS000285504100002.pdf10f3152f2dae29e39d6167e0d31b5ba9MD51open accessTEXTWOS000285504100002.pdf.txtWOS000285504100002.pdf.txtExtracted texttext/plain52065${dspace.ui.url}/bitstream/11600/32046/2/WOS000285504100002.pdf.txt05c85b60884cdb2d55a6f6d67e9fa909MD52open access11600/320462023-01-12 22:03:34.57open accessoai:repositorio.unifesp.br:11600/32046Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-01-13T01:03:34Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
title |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
spellingShingle |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer Da Silva, Leonard [UNIFESP] |
title_short |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
title_full |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
title_fullStr |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
title_full_unstemmed |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
title_sort |
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer |
author |
Da Silva, Leonard [UNIFESP] |
author_facet |
Da Silva, Leonard [UNIFESP] Simpson, Peter T. Smart, Chanel E. Cocciardi, Sibylle Waddell, Nic Lane, Annette Morrison, Brian J. Vargas, Ana Cristina Healey, Sue Beesley, Jonathan Pakkiri, Pria Parry, Suzanne Kurniawan, Nyoman Reid, Lynne Keith, Patricia Faria, Paulo Pereira, Emilio Skalova, Alena Bilous, Michael Balleine, Rosemary L. Do, Hongdo Dobrovic, Alexander Fox, Stephen Franco, Marcello [UNIFESP] Reynolds, Brent Khanna, Kum Kum Cummings, Margaret Chenevix-Trench, Georgia Lakhani, Sunil R. |
author_role |
author |
author2 |
Simpson, Peter T. Smart, Chanel E. Cocciardi, Sibylle Waddell, Nic Lane, Annette Morrison, Brian J. Vargas, Ana Cristina Healey, Sue Beesley, Jonathan Pakkiri, Pria Parry, Suzanne Kurniawan, Nyoman Reid, Lynne Keith, Patricia Faria, Paulo Pereira, Emilio Skalova, Alena Bilous, Michael Balleine, Rosemary L. Do, Hongdo Dobrovic, Alexander Fox, Stephen Franco, Marcello [UNIFESP] Reynolds, Brent Khanna, Kum Kum Cummings, Margaret Chenevix-Trench, Georgia Lakhani, Sunil R. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Univ Queensland Queensland Inst Med Res Universidade Federal de São Paulo (UNIFESP) Griffith Univ Eijkman Inst Inst Nacl Canc Lab Salomao & Zoppi Charles Univ Prague Univ Sydney Peter MacCallum Canc Ctr Royal Brisbane & Womens Hosp |
dc.contributor.author.fl_str_mv |
Da Silva, Leonard [UNIFESP] Simpson, Peter T. Smart, Chanel E. Cocciardi, Sibylle Waddell, Nic Lane, Annette Morrison, Brian J. Vargas, Ana Cristina Healey, Sue Beesley, Jonathan Pakkiri, Pria Parry, Suzanne Kurniawan, Nyoman Reid, Lynne Keith, Patricia Faria, Paulo Pereira, Emilio Skalova, Alena Bilous, Michael Balleine, Rosemary L. Do, Hongdo Dobrovic, Alexander Fox, Stephen Franco, Marcello [UNIFESP] Reynolds, Brent Khanna, Kum Kum Cummings, Margaret Chenevix-Trench, Georgia Lakhani, Sunil R. |
description |
Introduction: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear.Methods: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain.Results: Most brain metastases were triple negative and basal-like. the brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. in particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors.Conclusions: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. the need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules. |
publishDate |
2010 |
dc.date.issued.fl_str_mv |
2010-01-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T13:59:02Z |
dc.date.available.fl_str_mv |
2016-01-24T13:59:02Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Breast Cancer Research. London: Biomed Central Ltd, v. 12, n. 4, 13 p., 2010. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/32046 http://dx.doi.org/10.1186/bcr2603 |
dc.identifier.issn.none.fl_str_mv |
1465-542X |
dc.identifier.file.none.fl_str_mv |
WOS000285504100002.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1186/bcr2603 |
dc.identifier.wos.none.fl_str_mv |
WOS:000285504100002 |
identifier_str_mv |
Breast Cancer Research. London: Biomed Central Ltd, v. 12, n. 4, 13 p., 2010. 1465-542X WOS000285504100002.pdf 10.1186/bcr2603 WOS:000285504100002 |
url |
http://repositorio.unifesp.br/handle/11600/32046 http://dx.doi.org/10.1186/bcr2603 |
dc.language.iso.fl_str_mv |
eng |
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eng |
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Breast Cancer Research |
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openAccess |
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13 |
dc.publisher.none.fl_str_mv |
Biomed Central Ltd |
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Biomed Central Ltd |
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