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

Da Silva, Leonard, Simpson, Peter T., Smart, Chanek 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 and Lakhani, Sunil R. (2010) HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer. Breast Cancer Research, 12 4: R46-1-R46-11. doi:10.1186/bcr2603

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Author Da Silva, Leonard
Simpson, Peter T.
Smart, Chanek 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.
Title HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer
Journal name Breast Cancer Research   Check publisher's open access policy
ISSN 1465-5411
Publication date 2010
Sub-type Article (original research)
DOI 10.1186/bcr2603
Open Access Status DOI
Volume 12
Issue 4
Start page R46-1
End page R46-11
Total pages 11
Place of publication London, United Kingdom
Publisher Current Science
Collection year 2011
Language eng
Formatted 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.

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.

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.

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.
© 2010 Da 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.
Keyword Central-nervous-system
Neuregulin Expression
Colorectal Cancers
Primary Tumors
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article number R46, pp. 1-11

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Created: Sun, 30 Jan 2011, 00:06:38 EST