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

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Title HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer
Author Silva, Leonard Da; Simpson, Peter T; Smart, Chanel E; Cocciardi, Sibylle; Waddell, Nic; Lane, Annette; Morrison, Brian; 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; Chenevix-Trench, Georgia; Lakhani, Sunil R
Journal Name Breast Cancer Research
Year Published 2010
Place of publication United Kingdom
Publisher BioMed Central
Abstract 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 i
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1186/bcr2603
Copyright Statement Copyright 2010 Silva et al; licensee BioMed Central Ltd. 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.
Volume 12
Issue Number 4
Page from R46-1
Page to R46-13
ISSN 1465-5411
Date Accessioned 2011-05-04
Language en_US
Comments Page numbers are not for citation purposes. Instead, this article has the unique article number of 12.
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Cancer Cell Biology
URI http://hdl.handle.net/10072/38750
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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