ascochlorin and Breast-Neoplasms

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.

Topics: Alkenes; Animals; Antibiotics, Antineoplastic; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Longevity; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Phenols; Proto-Oncogene Proteins c-fos; Receptors, Estrogen; Survival Analysis; Tetrazolium Salts; Thiazoles; Transcription Factor AP-1; Xenograft Model Antitumor Assays

While agents targeting estrogen receptors are most effective in adjuvant therapy for human breast cancers expressing estrogen receptors after surgery, breast cancers lacking estrogen receptor are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Here, we found that MX-1, a human breast cancer cell line lacking estrogen receptors, exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos, and Fra-1 when compared with conventional estrogen receptor-positive human breast cancer cell lines. The prenylphenol antibiotic ascochlorin suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Our results suggest that AP-1 is an effective clinical target molecule for the treatment of estrogen receptor-negative human breast cancer.

Topics: Alkenes; Apoptosis; Blotting, Western; Breast Neoplasms; Caspases; Cell Line, Tumor; Cell Nucleus; Cell Survival; Coloring Agents; Cytochromes c; DNA Damage; Dose-Response Relationship, Drug; Genes, Reporter; Humans; Luciferases; Phenols; Plasmids; Receptors, Estrogen; Tetrazolium Salts; Thiazoles