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FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer

C T Karadedou1, A R Gomes, J Chen

  • 1Department of Surgery and Cancer, Cancer Research-UK Labs, Imperial College London, Hammersmith Hospital Campus, UK.

Oncogene
|August 24, 2011
PubMed

Insights

Forkhead box class O (FOXO)3a represses breast cancer growth by inhibiting vascular endothelial growth factor (VEGF) expression. Lapatinib activates FOXO3a, which displaces FOXM1 and reduces VEGF, thus controlling tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Vascular endothelial growth factor (VEGF) is crucial for breast cancer progression.
  • Mechanisms controlling VEGF expression in breast cancer are not fully understood.
  • An inverse correlation exists between Forkhead box class O (FOXO)3a and VEGF in breast cancer tissues.

Purpose of the Study:

  • To investigate the role of FOXO3a in regulating VEGF expression in breast cancer.
  • To elucidate the molecular mechanisms by which FOXO3a affects VEGF transcription.
  • To determine the effect of lapatinib on FOXO3a and VEGF signaling.

Main Methods:

  • Breast cancer cell lines (BT474, SKBR3) treated with lapatinib.
  • Transient transfection and inducible expression systems.
  • Chromatin immunoprecipitation and oligonucleotide pull-down assays.
  • Analysis of promoter activity, protein interactions, and histone acetylation.

Main Results:

  • Lapatinib induced nuclear translocation and activation of FOXO3a, reducing VEGF expression.
  • FOXO3a was found to repress the VEGF promoter, while FOXM1 induced it.
  • FOXO3a displaced FOXM1 from the VEGF promoter's Forkhead response element (FHRE).
  • Activated FOXO3a recruited histone deacetylase 2 (HDAC2), decreasing histone acetylation and inhibiting VEGF transcription.

Conclusions:

  • FOXO3a acts as a transcriptional repressor of VEGF in breast cancer cells.
  • VEGF regulation by FOXO3a involves competitive displacement of FOXM1 and recruitment of repressor complexes.
  • Targeting the FOXO3a pathway may offer a therapeutic strategy for breast cancer by controlling VEGF.

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