| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
Although agents targeting estrogen receptors(ER) are the most effective in adjuvant therapy for human breast cancer expressing ER after surgery, breast cancer lacking ER are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including ER-antagonists and DNA breaking agents. Apoptosis, on the other hand, can be induced by various stimuli such as the ligands of death receptors, chemotherapeutic drugs and irradiation. We found that the prenylphenol antibiotic ascochlorin(ASC) significantly induces typical apoptotic events in human breast cancer cells including cytochrome c release, activation of caspase-9, and -3, degradation of PARP and DNA fragmentation. In addition, we found that MX-1, a human breast cancer cell line lacking ER, exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos, and Fra-1 proteins as compared with ER-positive human breast cancer cell lines. When MX-1 or other human cell lines were treated with ASC, it dramatically suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells as compared with ER-positive cells at more than 500nM. When examining the death mechanism of MX-1 cells, they exhibited typical apoptosis features. From these results, it is suggested that AP-1 is an effective clinical target molecule for the treatment of estrogen receptor negative human breast cancer.
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