title: Interactions between αv-Integrin and HER2 and Their Role in the Invasive Phenotype of Breast Cancer Cells In Vitro and in Rat Brain.
abstract: BACKGROUND
  We tested the hypothesis that αv-integrin and the human epidermal growth factor receptor type 2 (HER2) interact with each other in brain trophic metastatic breast cancer cells and influence their invasive phenotype.
  
  
  METHODS
  Clones of MDA-MB231BR human breast cancer cells with stable knock down of αv-integrin in combination with high or low levels of HER2 were created. The interactions of these two proteins and their combined effect on cell migration and invasion were investigated in vitro and in vivo.
  
  
  RESULTS
  Knockdown of αv-integrin in MDA-MB231BR clones altered the actin cytoskeleton and cell morphology. HER2 co-precipitated with αv-integrin in three breast cancer cell lines in vitro, suggesting they complex in cells. Knockdown of αv-integrin altered HER2 localization from its normal membrane position to a predominantly lysosomal localization. When αv-integrin expression was decreased by 69-93% in HER2-expressing cells, cellular motility was significantly reduced. Deficiency of both αv-integrin and HER2 decreased cellular migration and invasion by almost 90% compared to cells expressing both proteins (P<0.01). After intracerebral inoculation, cells expressing high levels of both αv-integrin and HER2 showed a diffusely infiltrative tumor phenotype, while cells deficient in αv-integrin and/or HER2 showed a compact tumor growth phenotype. In the αv-integrin positive/HER2 positive tumors, infiltrative growth was 57.2 ± 19% of tumor volume, compared to only 5.8 ± 6.1% infiltration in the double deficient tumor cells.
  
  
  CONCLUSIONS
  αv-integrin interacts with HER2 in breast cancer cells and may regulate HER2 localization. The combined impacts of αv-integrin and HER2 influence the invasive phenotype of breast cancer cells. Targeting αv-integrin in HER2-positive breast cancer may slow growth and decrease infiltration in the normal brain.
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Sangeet
authors.initials: S
authors.lastname: Lal
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Cymon
authors.initials: C
authors.lastname: Kersch
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Beeson
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Y Jeffrey
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America; Department of Cell, Developmental and Cancer Biology, Oregon Health & Sciences University, Portland, Oregon, United States of America.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Muldoon
authors.affiliation: Department of Neurology, Oregon Health & Sciences University, Portland, Oregon, United States of America; Department of Neurosurgery, Oregon Health & Sciences University, Portland, Oregon, United States of America; Veterans Administration Medical Center (EAN), Portland, Oregon, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D039564:Integrin alphaV; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human