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

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Date
2010-01-01Author
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.
Type
ArtigoISSN
1465-542XIs part of
Breast Cancer ResearchDOI
10.1186/bcr2603Metadata
Show full item recordAbstract
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.
Citation
Breast Cancer Research. London: Biomed Central Ltd, v. 12, n. 4, 13 p., 2010.Sponsorship
Ludwig Institute of Cancer ResearchNational Breast Cancer Foundation
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