Aberrant expression of Fra-1 in estrogen receptor-negative breast cancers and suppression of their propagation in vivo by ascochlorin, an antibiotic that inhibits cellular activator protein-1 activity

J Antibiot (Tokyo). 2007 Nov;60(11):682-9. doi: 10.1038/ja.2007.87.

Abstract

Estrogen receptor-negative breast cancers generally are highly malignant, resistant to chemotherapy and poorly prognostic. Here we demonstrate that estrogen receptor-negative human breast cancer cell lines highly express Fra-1, c-Fos and c-Jun, components of the transcription factor, activator protein-1 (AP-1). Retrospective observation of breast cancer tissues obtained by core needle biopsy before surgery from stages II and III patients demonstrates that Fra-1 expression is high in estrogen receptor-negative human breast cancers, and negatively correlated to paclitaxel sensitivity. Ascochlorin, which suppresses cellular AP-1 activity, selectively kills estrogen receptor-negative human and mouse breast cancer cell lines, and prolongs the survival time of mice implanted with an estrogen receptor-negative mammary carcinoma. These results suggest that chemotherapy targeting AP-1 activity is a potent strategy for estrogen receptor-negative human breast cancers.

MeSH terms

  • Alkenes / pharmacology*
  • Alkenes / therapeutic use
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Antibiotics, Antineoplastic / therapeutic use
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Longevity
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Transplantation
  • Phenols / pharmacology*
  • Phenols / therapeutic use
  • Proto-Oncogene Proteins c-fos / biosynthesis*
  • Receptors, Estrogen / metabolism*
  • Survival Analysis
  • Tetrazolium Salts
  • Thiazoles
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • Alkenes
  • Antibiotics, Antineoplastic
  • Phenols
  • Proto-Oncogene Proteins c-fos
  • Receptors, Estrogen
  • Tetrazolium Salts
  • Thiazoles
  • Transcription Factor AP-1
  • fos-related antigen 1
  • thiazolyl blue
  • ascochlorin