title: Understanding Heterogeneity and Permeability of Brain Metastases in Murine Models of HER2-Positive Breast Cancer Through Magnetic Resonance Imaging: Implications for Detection and Therapy.
abstract: OBJECTIVE
  Brain metastases due to breast cancer are increasing, and the prognosis is poor. Lack of effective therapy is attributed to heterogeneity of breast cancers and their resulting metastases, as well as impermeability of the blood-brain barrier (BBB), which hinders delivery of therapeutics to the brain. This work investigates three experimental models of HER2+ breast cancer brain metastasis to better understand the inherent heterogeneity of the disease. We use magnetic resonance imaging (MRI) to quantify brain metastatic growth and explore its relationship with BBB permeability.
  
  
  METHODS
  Brain metastases due to breast cancer cells (SUM190-BR3, JIMT-1-BR3, or MDA-MB-231-BR-HER2) were imaged at 3 T using balanced steady-state free precession and contrast-enhanced T1-weighted spin echo sequences. The histology and immunohistochemistry corresponding to MRI were also analyzed.
  
  
  RESULTS
  There were differences in metastatic tumor appearance by MRI, histology, and immunohistochemistry (Ki67, CD31, CD105) across the three models. The mean volume of an MDA-MB-231-BR-HER2 tumor was significantly larger compared to other models (F2,12 = 5.845, P < .05); interestingly, this model also had a significantly higher proportion of Gd-impermeable tumors (F2,12 = 22.18, P < .0001). Ki67 staining indicated that Gd-impermeable tumors had significantly more proliferative nuclei compared to Gd-permeable tumors (t[24] = 2.389, P < .05) in the MDA-MB-231-BR-HER2 model. CD31 and CD105 staining suggested no difference in new vasculature patterns between permeable and impermeable tumors in any model.
  
  
  CONCLUSIONS
  Significant heterogeneity is present in these models of brain metastases from HER2+ breast cancer. Understanding this heterogeneity, especially as it relates to BBB permeability, is important for improvement in brain metastasis detection and treatment delivery.
authors.affiliation: Imaging, Robarts Research Institute, London, Ontario, Canada; Medical Biophysics, Western University, London, Ontario, Canada. Electronic address: dmurrell@robarts.ca.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Murrell
authors.affiliation: Imaging, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Hamilton
authors.affiliation: Imaging, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Christiane L
authors.initials: CL
authors.lastname: Mallett
authors.affiliation: Imaging, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Robbert
authors.initials: R
authors.lastname: van Gorkum
authors.affiliation: Medical Biophysics, Western University, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.affiliation: Imaging, Robarts Research Institute, London, Ontario, Canada; Medical Biophysics, Western University, London, Ontario, Canada.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Foster