β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer

• Published in: Science signaling 2014-02, Vol.7 (312), p.ra15
• Main Authors: Truong, Hoa H, Xiong, Jiangling, Ghotra, Veerander P S, Nirmala, Ella, Haazen, Lizette, Le Dévédec, Sylvia E, Balcioğlu, Hayri E, He, Shuning, Snaar-Jagalska, B Ewa, Vreugdenhil, Erno, Meerman, John H N, van de Water, Bob, Danen, Erik H J
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Cadherins - metabolism; Cell Line, Tumor; Cell Movement - physiology; DNA-Binding Proteins - genetics; Extracellular Matrix - metabolism; Flow Cytometry; Gene Silencing; Homeodomain Proteins - metabolism; Humans; Immunohistochemistry; Integrin beta1 - genetics; Integrin beta1 - metabolism; Luciferases; Lung Neoplasms - secondary; Mice; Mice, Knockout; MicroRNAs - metabolism; Neoplasm Metastasis - physiopathology; Repressor Proteins - metabolism; Signal Transduction - physiology; Time-Lapse Imaging; Transforming Growth Factor beta - metabolism; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - physiopathology; Zebrafish; Zinc Finger E-box Binding Homeobox 2
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.2004751

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.