Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling

Cancer Cell. 2019 Jan 14;35(1):64-80.e7. doi: 10.1016/j.ccell.2018.11.016. Epub 2019 Jan 3.


Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.

Keywords: EGFR; FAK; Tinagl1; extracellular matrix; integrin; metastasis; triple-negative breast cancer; tumor-stromal interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • ErbB Receptors / metabolism
  • Extracellular Matrix Proteins / administration & dosage
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrin alpha5beta1 / metabolism*
  • Lipocalins / administration & dosage
  • Lipocalins / genetics*
  • Lipocalins / metabolism
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy*
  • Mice
  • Prognosis
  • Receptors, Vitronectin / metabolism*
  • Signal Transduction
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / therapy*


  • Biomarkers, Tumor
  • Extracellular Matrix Proteins
  • Integrin alpha5beta1
  • Lipocalins
  • Receptors, Vitronectin
  • TINAGL1 protein, human
  • integrin alphavbeta1
  • EGFR protein, human
  • ErbB Receptors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human