Cargando…

HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer

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 som...

Descripción completa

Detalles Bibliográficos
Autores principales: Da Silva, Leonard, 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, Reynolds, Brent, Khanna, Kum Kum, Cummings, Margaret, Chenevix-Trench, Georgia, Lakhani, Sunil R
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949633/
https://www.ncbi.nlm.nih.gov/pubmed/20604919
http://dx.doi.org/10.1186/bcr2603
_version_ 1782187540625752064
author Da Silva, Leonard
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
Reynolds, Brent
Khanna, Kum Kum
Cummings, Margaret
Chenevix-Trench, Georgia
Lakhani, Sunil R
author_facet Da Silva, Leonard
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
Reynolds, Brent
Khanna, Kum Kum
Cummings, Margaret
Chenevix-Trench, Georgia
Lakhani, Sunil R
author_sort Da Silva, Leonard
collection PubMed
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.
format Text
id pubmed-2949633
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-29496332010-10-06 HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer Da Silva, Leonard 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 Reynolds, Brent Khanna, Kum Kum Cummings, Margaret Chenevix-Trench, Georgia Lakhani, Sunil R Breast Cancer Res Research Article 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. BioMed Central 2010 2010-07-06 /pmc/articles/PMC2949633/ /pubmed/20604919 http://dx.doi.org/10.1186/bcr2603 Text en Copyright ©2010 Da Silva et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Da Silva, Leonard
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
Reynolds, Brent
Khanna, Kum Kum
Cummings, Margaret
Chenevix-Trench, Georgia
Lakhani, Sunil R
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
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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949633/
https://www.ncbi.nlm.nih.gov/pubmed/20604919
http://dx.doi.org/10.1186/bcr2603
work_keys_str_mv AT dasilvaleonard her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT simpsonpetert her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT smartchanele her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT cocciardisibylle her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT waddellnic her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT laneannette her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT morrisonbrianj her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT vargasanacristina her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT healeysue her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT beesleyjonathan her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT pakkiripria her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT parrysuzanne her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT kurniawannyoman her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT reidlynne her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT keithpatricia her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT fariapaulo her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT pereiraemilio her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT skalovaalena her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT bilousmichael her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT balleinerosemaryl her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT dohongdo her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT dobrovicalexander her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT foxstephen her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT francomarcello her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT reynoldsbrent her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT khannakumkum her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT cummingsmargaret her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT chenevixtrenchgeorgia her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer
AT lakhanisunilr her3anddownstreampathwaysareinvolvedincolonizationofbrainmetastasesfrombreastcancer