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.
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.
Nakajima
Hiroo
H
Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kamikyo-ku, Kyoto, Japan.
Mizuta
Naruhiko
N
Sakaguchi
Koichi
K
Fujiwara
Ikuya
I
Mizuta
Mitsuhiko
M
Furukawa
Chiharu
C
Chang
Young-Chae
YC
Magae
Junji
J
D000475:Alkenes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008136:Longevity; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000378:metabolism*; D016019:Survival Analysis; D013778:Tetrazolium Salts; D013844:Thiazoles; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D000099169:Fos-Related Antigen 1
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D010636:Phenols; D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D013778:Tetrazolium Salts; D013844:Thiazoles; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C022616:thiazolyl blue; C415745:ascochlorin