Heterogeneity between triple negative breast cancer cells due to differential activation of Wnt and PI3K/AKT pathways

Exp Cell Res. 2015 Nov 15;339(1):67-80. doi: 10.1016/j.yexcr.2015.10.006. Epub 2015 Oct 21.

Abstract

The lack of a successful treatment for triple-negative breast cancer demands the study of the heterogeneity of cells that constitute these tumors. With this aim, two clones from triple negative breast MDA-MB-231 cancer cells were isolated: One with fibroblast-like appearance (F) and another with semi-epithelial (SE) morphology. Cells of the F clone have a higher migration and tumorigenesis capacity than SE cells, suggesting that these cells are in a more advanced stage of epithelial to mesenchymal transformation. In agreement, F cells have a diminished expression of the tight junction proteins claudins 1 and 4, and an increased content of β-catenin. The latter is due to an augmented activity of the canonical Wnt route and of the EGFR/PI3K/mTORC2/AKT pathway favoring the cytoplasmic accumulation of β-catenin and its transcriptional activity. In addition, F cells display increased phosphorylation of β-catenin at Tyr654 by Src. These changes favor in F cells, the over-expression of Snail that promotes EMT. Finally, we observe that both F and SE cells display markers of cancer stem cells, which are more abundant in the F clone.

Keywords: AKT; Cancer cells heterogeneity; Triple negative breast cancer; Wnt; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Chemotaxis
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Nude
  • Multiprotein Complexes / metabolism*
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Cells, Cultured
  • Wnt Proteins / metabolism*
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*

Substances

  • Multiprotein Complexes
  • Wnt Proteins
  • beta Catenin
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt