Protein expression changes during human triple negative breast cancer cell line progression to lymph node metastasis in a xenografted model in nude mice.

  • Roberti M
  • Arriaga J
  • Bianchini M
 et al. 
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Triple negative breast cancers (TNBC) lacking hormone receptors and HER-2 amplification are very aggressive tumors. Since relevant differences between primary tumors and metastases could arise during tumor progression as evidenced by phenotypic discordances reported for hormonal receptors or HER-2 expression, in this analysis we studied changes that occurred in our TNBC model IIB-BR-G throughout the development of IIB-BR-G-MTS6 metastasis to the lymph nodes (LN) in nude mice, using an antibody-based protein array to characterize their expression profile. We also analyzed their growth kinetics, migration, invasiveness and cytoskeleton structure in vitro and in vivo. In vitro IIB-BR-G-MTS6 cells grew slower but showed higher anchorage independent growth. In vivo IIB-BR-G-MTS6 tumors grew significantly faster and showed a 100% incidence of LN metastasis after s.c. inoculation, although no metastasis was observed for IIB-BR-G. CCL3, IL1beta, CXCL1, CSF2, CSF3, IGFBP1, IL1alpha, IL6, IL8, CCL20, PLAUR, PlGF and VEGF were strongly upregulated in IIB-BR-G-MTS6 while CCL4, ICAM3, CXCL12, TNFRSF18, FIGF were the most downregulated proteins in the metastatic cell line. IIB-BR-G-MTS6 protein expression profile could reflect a higher NFkappaB activation in these cells. In vitro, IIB-BR-G displayed higher migration but IIB-BR-G-MTS6 had more elevated matrigel invasion ability. In agreement with that observation, IIB-BR-G-MTS6 had an upregulated expression of MMP1, MMP9, MMP13, PLAUR and HGF. IIB-BR-G-MTS6 tumors presented also higher local lymphatic invasion than IIB-BR-G but similar lymphatic vessel densities. VEGFC and VEGFA/B expression were higher both in vitro and in vivo for IIB-BR-G-MTS6. IIB-BR-G-MTS6 expressed more vimentin than IB-BR-G cells, which was mainly localized in the cellular extremities and both cell lines are E-cadherin negative. Our results suggest that IIB-BR-G-MTS6 cells have acquired a pronounced epithelial-to-mesenchymal transition phenotype. Protein expression changes observed between primary tumor-derived IIB-BR-G and metastatic IIB-BR-G-MTS6 TNBC cells suggest potential targets involved in the control of metastasis.

Author-supplied keywords

  • Animals
  • Breast Neoplasms
  • Cell Line
  • Cell Proliferation
  • Disease Progression
  • ErbB-2
  • Estrogen
  • Female
  • Heterologous
  • Humans
  • Immunohistochemistry
  • Lymphatic Metastasis
  • Mice
  • Neoplasm Proteins
  • Nude
  • Progesterone
  • Receptor
  • Receptors
  • Transplantation
  • Tumor
  • Vimentin
  • biosynthesis
  • genetics
  • metabolism
  • pathology

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  • Maria Paula Roberti

  • Juan Martin Arriaga

  • Michele Bianchini

  • Hector Ramiro Quinta

  • Alicia Ines Bravo

  • Estrella Mariel Levy

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