Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Anoikis / drug effects
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Apoptosis / drug effects
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Bcl-2-Like Protein 11 / antagonists & inhibitors
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Bcl-2-Like Protein 11 / genetics
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Bcl-2-Like Protein 11 / metabolism
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Breast Neoplasms / drug therapy
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology*
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Cadherins / genetics
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Cadherins / metabolism*
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Cell Line, Tumor
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Doxycycline / pharmacology
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Doxycycline / therapeutic use
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Female
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Forkhead Box Protein O3 / metabolism*
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Humans
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Lung Neoplasms / pathology
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Lung Neoplasms / secondary
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MCF-7 Cells
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Signal Transduction
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Transcriptional Activation
Substances
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Adaptor Proteins, Signal Transducing
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Bcl-2-Like Protein 11
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Bmf protein, mouse
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Cadherins
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Forkhead Box Protein O3
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Doxycycline