TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin

Cell Cycle. 2012 Aug 1;11(15):2922-30. doi: 10.4161/cc.21386. Epub 2012 Aug 1.

Abstract

The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis.

Publication types

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

MeSH terms

  • Amphiregulin
  • Breast Neoplasms / metabolism*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic*
  • EGF Family of Proteins
  • Epithelial Cells / metabolism
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / metabolism*
  • Female
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ligands
  • Mammary Glands, Human / metabolism*
  • Mammary Glands, Human / pathology
  • Neoplasm Metastasis
  • Nuclear Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Trans-Activators
  • Transcription Factors

Substances

  • AREG protein, human
  • Amphiregulin
  • Cell Cycle Proteins
  • EGF Family of Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Nuclear Proteins
  • RNA, Small Interfering
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • YY1AP1 protein, human
  • EGFR protein, human
  • ErbB Receptors