FADD phosphorylation is critical for cell cycle regulation in breast cancer cells.
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.
Matsuyoshi
S
S
Department of Pathology, Nara Medical University School of Medicine, Nara 634-8521, Japan. smatsu@naramed-u.ac.jp
Shimada
K
K
Nakamura
M
M
Ishida
E
E
Konishi
N
N
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism* / Q000502:physiology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000503:physiopathology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011960:Receptors, Estrogen; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011960:Receptors, Estrogen; D013629:Tamoxifen; D048031:JNK Mitogen-Activated Protein Kinases; D017239:Paclitaxel