Clinical and Translational Oncology

, Volume 16, Issue 11, pp 937–941

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets

  • S. Ramon y Cajal
  • L. De Mattos-Arruda
  • N. Sonenberg
  • J. Cortes
  • V. Peg
EDUCATIONAL SERIES – BLUE SERIES Advances in Translational Oncology

DOI: 10.1007/s12094-014-1203-9

Cite this article as:
Ramon y Cajal, S., De Mattos-Arruda, L., Sonenberg, N. et al. Clin Transl Oncol (2014) 16: 937. doi:10.1007/s12094-014-1203-9


Breast cancers and most malignant tumors are composed of heterogeneous tumor cells both at genetic and morphological levels; intra-tumor heterogeneity can be one underlying cause of therapeutic resistance. Classical studies have focused on analyses of the relationship between primary tumors and metastatic dissemination, and on subclone evolution. However, it should be noted that tumor heterogeneity at the level of protein expression (proteomics) has not been yet studied in depth. The differences in protein expression also can play an important role in elucidating the relationship between intra-tumor heterogeneity and resistance to systemic therapy. In fact, in human tumors there is not always a homogeneous expression of many of the crucial factors involved in cell signaling, such as pMAPK, pAKt, pMTOR, even with constitutive oncogenic alterations upstream, such as HER2, PI3 K. Conversely, two of these factors, peIF4E and p4E-BP1, which are downstream, and control protein translation, show a diffuse and strong protein expression. In summary, most of cell signaling factors show a heterogeneous expression, regardless of oncogenic alterations. Tissue heterogeneity could be driven by local factors, including hypoxia. The fact that the phosphorylation of crucial proteins such as 4E-BP1 and eIF4E is observed homogeneously throughout most tumors and are druggable opens the chance to get real potential targets in cancer therapy.


Breast cancer Intra-tumor heterogeneity Proteomics 



4E-binding protein 1


V-aktmurinethymoma viral oncogene homolog


Eukaryotic translation initiation factor 4E


Extracellular-signal-regulated kinase


Fluorescence in situ hybridization


Mitogen-activated protein kinase


Mammalian target of rapamycin


Phosphoinositide 3-kinase




Ribosomal protein S6

Supplementary material

12094_2014_1203_MOESM1_ESM.jpg (39 kb)
Supplementary Figure S1. Heterogeneity of cell signaling factors in breast carcinomas: focal vs diffuse cellular expression (JPEG 38 kb)
12094_2014_1203_MOESM2_ESM.doc (38 kb)
Supplementary Table S1. Primary antibodies used (DOC 38 kb)

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2014

Authors and Affiliations

  • S. Ramon y Cajal
    • 1
    • 2
  • L. De Mattos-Arruda
    • 2
    • 3
  • N. Sonenberg
    • 4
  • J. Cortes
    • 3
    • 5
  • V. Peg
    • 1
    • 2
  1. 1.Pathology DepartmentVall d’Hebron University HospitalBarcelonaSpain
  2. 2.Universitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Medical Oncology DepartmentVall d’Hebron Institute of Oncology, Vall d’Hebron University HospitalBarcelonaSpain
  4. 4.Department of Biochemistry and McGill Cancer CenterMcGill University, Goodman Cancer CentreMontrealCanada
  5. 5.Medica Scientia Innovation Research (MedSIR)BarcelonaSpain

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