FADD phosphorylation is critical for cell cycle regulation in breast cancer cells

Br J Cancer. 2006 Feb 27;94(4):532-9. doi: 10.1038/sj.bjc.6602955.


Anti-oestrogen therapy is effective for control of hormone receptor-positive breast cancers, although the detailed molecular mechanisms, including signal transduction, remain unclear. We demonstrated here that long-term tamoxifen treatment causes G2/M cell cycle arrest through c-jun N-terminal kinase (JNK) activation, which is dependent on phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine in an oestrogen (ER) receptor-positive breast cancer cell line, MCF-7. Expression of a dominant negative mutant form of MKK7, a kinase upstream of JNK, or mutant FADD (S194A) in MCF-7 cells suppressed the cytotoxicity of long-term tamoxifen treatment. Of great interest, similar signallings could be evoked by paclitaxel, even in an ER-negative cell line, MDA-MB-231. In addition, immunohistochemical analysis using human breast cancer specimens showed a close correlation between phosphorylated JNK and FADD expression, both being significantly reduced in cases with metastatic potential. We conclude that JNK-mediated phosphorylation of FADD plays an important role in the negative regulation of cell growth and metastasis, independent of the ER status of a breast cancer, so that JNK/FADD signals might be promising targets for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adaptor Proteins, Signal Transducing / physiology*
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Breast Neoplasms / pathology*
  • Cell Cycle / physiology*
  • Fas-Associated Death Domain Protein
  • Female
  • Humans
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Middle Aged
  • Neoplasm Metastasis / physiopathology
  • Paclitaxel / pharmacology
  • Phosphorylation
  • Receptors, Estrogen
  • Signal Transduction
  • Tamoxifen / pharmacology
  • Tumor Cells, Cultured


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Hormonal
  • Antineoplastic Agents, Phytogenic
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Receptors, Estrogen
  • Tamoxifen
  • JNK Mitogen-Activated Protein Kinases
  • Paclitaxel