title: HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer.
abstract: 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.
authors.affiliation: Molecular & Cellular Pathology, The University of Queensland Centre for Clinical Research, & School of Medicine, Building 918/B71, RBWH complex, Brisbane, 4029, Australia.
authors.forename: Leonard
authors.initials: L
authors.lastname: Da Silva
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.forename: Chanel E
authors.initials: CE
authors.lastname: Smart
authors.forename: Sibylle
authors.initials: S
authors.lastname: Cocciardi
authors.forename: Nic
authors.initials: N
authors.lastname: Waddell
authors.forename: Annette
authors.initials: A
authors.lastname: Lane
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morrison
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Vargas
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.forename: Pria
authors.initials: P
authors.lastname: Pakkiri
authors.forename: Suzanne
authors.initials: S
authors.lastname: Parry
authors.forename: Nyoman
authors.initials: N
authors.lastname: Kurniawan
authors.forename: Lynne
authors.initials: L
authors.lastname: Reid
authors.forename: Patricia
authors.initials: P
authors.lastname: Keith
authors.forename: Paulo
authors.initials: P
authors.lastname: Faria
authors.forename: Emilio
authors.initials: E
authors.lastname: Pereira
authors.forename: Alena
authors.initials: A
authors.lastname: Skalova
authors.forename: Michael
authors.initials: M
authors.lastname: Bilous
authors.forename: Rosemary L
authors.initials: RL
authors.lastname: Balleine
authors.forename: Hongdo
authors.initials: H
authors.lastname: Do
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.forename: Marcello
authors.initials: M
authors.lastname: Franco
authors.forename: Brent
authors.initials: B
authors.lastname: Reynolds
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Margaret
authors.initials: M
authors.lastname: Cummings
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
mesh_terms: 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
chemical_list: 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