title: Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.
abstract: BACKGROUND
  An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.
  
  
  RESULTS
  Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.
  
  
  CONCLUSIONS
  Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.
authors: Andrés
authors: A
authors: Castellanos-Martín
authors: Sonia
authors: S
authors: Castillo-Lluva
authors: María Del Mar
authors: Mdel M
authors: Sáez-Freire
authors: Adrián
authors: A
authors: Blanco-Gómez
authors: Lourdes
authors: L
authors: Hontecillas-Prieto
authors: Carmen
authors: C
authors: Patino-Alonso
authors: Purificación
authors: P
authors: Galindo-Villardon
authors: Luis
authors: L
authors: Pérez Del Villar
authors: Carmen
authors: C
authors: Martín-Seisdedos
authors: María
authors: M
authors: Isidoro-Garcia
authors: María Del Mar
authors: MM
authors: Abad-Hernández
authors: Juan Jesús
authors: JJ
authors: Cruz-Hernández
authors: César Augusto
authors: CA
authors: Rodríguez-Sánchez
authors: Rogelio
authors: R
authors: González-Sarmiento
authors: Diego
authors: D
authors: Alonso-López
authors: Javier
authors: J
authors: De Las Rivas
authors: Begoña
authors: B
authors: García-Cenador
authors: Javier
authors: J
authors: García-Criado
authors: Do Yup
authors: DY
authors: Lee
authors: Benjamin
authors: B
authors: Bowen
authors: Wolfgang
authors: W
authors: Reindl
authors: Trent
authors: T
authors: Northen
authors: Jian-Hua
authors: JH
authors: Mao
authors: Jesús
authors: J
authors: Pérez-Losada
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D049490:Systems Biology
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C494918:AKT1 protein, human