The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer

Oncogene. 2017 Jun 15;36(24):3490-3503. doi: 10.1038/onc.2016.492. Epub 2017 Jan 30.


The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin downregulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.

MeSH terms

  • Animals
  • Antigens, CD
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Female
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Intercellular Junctions
  • MCF-7 Cells
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Prognosis
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Zinc Finger E-box Binding Homeobox 2


  • ARHGAP31 protein, human
  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • GTPase-Activating Proteins
  • Homeodomain Proteins
  • Phosphoproteins
  • Repressor Proteins
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2