HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.
BACKGROUND
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.
Da Silva
Leonard
L
Molecular & Cellular Pathology, The University of Queensland Centre for Clinical Research, & School of Medicine, Building 918/B71, RBWH complex, Brisbane, 4029, Australia.
Simpson
Peter T
PT
Smart
Chanel E
CE
Cocciardi
Sibylle
S
Waddell
Nic
N
Lane
Annette
A
Morrison
Brian J
BJ
Vargas
Ana Cristina
AC
Healey
Sue
S
Beesley
Jonathan
J
Pakkiri
Pria
P
Parry
Suzanne
S
Kurniawan
Nyoman
N
Reid
Lynne
L
Keith
Patricia
P
Faria
Paulo
P
Pereira
Emilio
E
Skalova
Alena
A
Bilous
Michael
M
Balleine
Rosemary L
RL
Do
Hongdo
H
Dobrovic
Alexander
A
Fox
Stephen
S
Franco
Marcello
M
Reynolds
Brent
B
Khanna
Kum Kum
KK
Cummings
Margaret
M
Chenevix-Trench
Georgia
G
Lakhani
Sunil R
SR
D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins