Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

Cell Death Differ. 2016 Sep 1;23(9):1483-92. doi: 10.1038/cdd.2016.33. Epub 2016 Apr 1.


Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Anoikis / drug effects
  • Apoptosis / drug effects
  • Bcl-2-Like Protein 11 / antagonists & inhibitors
  • Bcl-2-Like Protein 11 / genetics
  • Bcl-2-Like Protein 11 / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Doxycycline / pharmacology
  • Doxycycline / therapeutic use
  • Female
  • Forkhead Box Protein O3 / metabolism*
  • Humans
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • MCF-7 Cells
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction
  • Transcriptional Activation


  • Adaptor Proteins, Signal Transducing
  • Bcl-2-Like Protein 11
  • Bmf protein, mouse
  • Cadherins
  • Forkhead Box Protein O3
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Doxycycline