Research article
HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer
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* Corresponding author: Sunil R Lakhani s.lakhani@uq.edu.au
1 Molecular & Cellular Pathology, The University of Queensland Centre for Clinical Research, & School of Medicine, Building 918/B71, RBWH complex, Brisbane, 4029, Australia
2 Cancer Genetics and Molecular Pathology, The Queensland Institute of Medical Research, 300 Herston Road, Brisbane, 4006, Australia
3 Departamento de Anatomia Patológica, Universidade Federal de São Paulo, EPM, 754 Rua Napoleão de Barros, São Paulo, 04024-000, Brazil
4 Biomolecular and Biomedical Science, Griffith University, 170 Kessels Road, Brisbane, 4011, Australia
5 Centre for Magnetic Resonance, The University of Queensland, St Lucia, Brisbane, 4072, Australia
6 Lembaga Eijkman, Eijkman Institute, Diponegoro 69, Jakarta, 10430, Indonesia
7 Departamento de Patologia, Instituto Nacional de Câncer, 23 Praça Cruz Vermelha, Rio de Janeiro, 20230-130, Brazil
8 Departamento de Patologia, Laboratório Salomão & Zoppi, 48 Rua Correia Dias, São Paulo, 04104-000, Brazil
9 Department of Pathology, Medical Faculty of Charles University in Plzen, Husova 3, 306 05, Czech Republic
10 Sydney West Area Health Service, Institute of Clinical Pathology and Medical Research, University of Sydney, Darcy Road, Sydney, 2145, Australia
11 Translational Oncology, Sydney West Area Health Service, Westmead Millennium Institute, University of Sydney, Darcy Road, Sydney, 2145, Australia
12 Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Pl, East Melbourne, 3002, Australia
13 Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, 4072, Australia
14 Signal Transduction, The Queensland Institute of Medical Research, 300 Herston Road, Brisbane, 4006, Australia
15 Pathology Queensland: The Royal Brisbane & Women's Hospital, Herston Road, Brisbane, 4029, Australia
16 Current address - University of Florida, McKnight Brain Institute,100 S. Newell Drive, Gainesville, 32611, USA
Breast Cancer Research 2010, 12:R46 doi:10.1186/bcr2603
Published: 6 July 2010Abstract
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.