title: β1 integrin inhibition elicits a prometastatic switch through the TGFβ-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer.
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.
authors: 1Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333CC, the Netherlands.
authors: Hoa H
authors: HH
authors: Truong
authors: Jiangling
authors: J
authors: Xiong
authors: Veerander P S
authors: VP
authors: Ghotra
authors: Ella
authors: E
authors: Nirmala
authors: Lizette
authors: L
authors: Haazen
authors: Sylvia E
authors: SE
authors: Le Dévédec
authors: Hayri E
authors: HE
authors: Balcioğlu
authors: Shuning
authors: S
authors: He
authors: B Ewa
authors: BE
authors: Snaar-Jagalska
authors: Erno
authors: E
authors: Vreugdenhil
authors: John H N
authors: JH
authors: Meerman
authors: Bob
authors: B
authors: van de Water
authors: Erik H J
authors: EH
authors: Danen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005434:Flow Cytometry; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D059008:Time-Lapse Imaging; D016212:Transforming Growth Factor beta / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D015027:Zebrafish; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D019012:Integrin beta1; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; C499308:Rag2 protein, mouse; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D008156:Luciferases