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

Abstract

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.

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Acknowledgements

We thank Dr Patricia Tonin for helpful discussions and Dr John J Bergeron for critically reading this manuscript. We are grateful to Dr Morag Park (McGill University) for providing the Zeb2 and E-cadherin-luc constructs. We thank Dr Torsten Nielsen for providing the human breast cancer TMA and the CdGAP IHC staining through the Genetic Pathology Evaluation Center (GPEC), ZF Dong for IHC staining of primary tumors, Dr Min Fu for assistance with confocal microscopy at the imaging platform of the RI-MUHC, Martin Primeau and Vilayphone Luangrath for affinity purification of the CdGAP antibodies. NL-V was a recipient of a FRSQ chercheur-national and a William Dawson scholar. Canadian Institute for Health Research (CIHR) MOP-119544 to NL-V and MOP- 144425 to JFC. JFC is a recipient of a FRQS senior scholarship.

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Correspondence to N Lamarche-Vane.

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He, Y., Northey, J., Pelletier, A. et al. The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer. Oncogene 36, 3490–3503 (2017). https://doi.org/10.1038/onc.2016.492

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