Original Article | Published:

Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression

Oncogene volume 36, pages 11571166 (23 February 2017) | Download Citation

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Abstract

The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal breast cancer (LBC) with good prognosis, whereas Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis owing to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which has an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to Foxa1 proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA polymerase II recruitment. Twist1 also silences Foxa1 promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1’s silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis, but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.

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Acknowledgements

We thank Yuqing Xiong for assisting with manuscript preparation and the Genetically Engineered Mouse Core (GEMC) partially supported by the National Institutes of Health (NIH) grant P30CA125123 at Baylor College of Medicine for assisting with mouse models. This study is supported by NIH grants CA112403 and CA193455 and Cancer Prevention and Research Institute of Texas grants RP120732-P5 and RP150197. This study is also partially supported by National Natural Science Foundation of China grants 81572619 and Sichuan Education Department research grant 15TD0020.

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Affiliations

  1. Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    • Y Xu
    • , L Qin
    • , T Sun
    • , H Wu
    • , L Liao
    •  & J Xu
  2. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA

    • Y Xu
  3. Institution for Cancer Medicine and College of Basic Medical Sciences, Southwest Medical University, Luzhou, China

    • T He
    • , Z Yang
    •  & J Xu
  4. Department of Medicine-Hematology/Oncology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    • Q Mo

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The authors declare no conflict of interest.

Corresponding author

Correspondence to J Xu.

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https://doi.org/10.1038/onc.2016.286

Supplementary Information accompanies this paper on the Oncogene website (http://www.nature.com/onc)

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