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Sci. Signal., 11 February 2014
Vol. 7, Issue 312, p. ra15
[DOI: 10.1126/scisignal.2004751]

RESEARCH ARTICLES

β1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer

Hoa H. Truong1*, Jiangling Xiong1*, Veerander P. S. Ghotra1, Ella Nirmala1, Lizette Haazen1, Sylvia E. Le Dévédec1, Hayri E. Balcioğlu1, Shuning He2, B. Ewa Snaar-Jagalska2, Erno Vreugdenhil3, John H. N. Meerman1, Bob van de Water1, and Erik H. J. Danen1{dagger}

1 Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333CC, the Netherlands.
2 Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden 2333CC, the Netherlands.
3 Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333CC, the Netherlands.

* These authors contributed equally to this work.

Abstract: Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the β1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of β1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked β1 integrin function or knockdown of β1 switched the migratory behavior of human and mouse E-cadherin–positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor–β (TGFβ) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box–binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFβ receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in β1 integrin–deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that β1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting β1 integrins may have undesirable effects in TNBC.

{dagger} Corresponding author. E-mail: e.danen{at}lacdr.leidenuniv.nl

Citation: H. H. Truong, J. Xiong, V. P. S. Ghotra, E. Nirmala, L. Haazen, S. E. Le Dévédec, H. E. Balcioğlu, S. He, B. E. Snaar-Jagalska, E. Vreugdenhil, J. H. N. Meerman, B. van de Water, E. H. J. Danen, β1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer. Sci. Signal. 7, ra15 (2014).

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