| Project/Area Number |
12213132
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | 藤田保健衛生大学 |
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Principal Investigator |
HARADA Nobuhiro Fujita Health University School of Medicine, Professor, 医学部, 教授 (00189705)
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| Co-Investigator(Kenkyū-buntansha) |
HONDA Shin-ichiro Fujita Health University School of Medicine, Lecturer, 医学部, 講師 (40257639)
UTSUMI Toshiaki Fujita Health University School of Medicine, Associate Professor, 医学部, 助教授 (10176711)
HAYASHI Shin-ichi Saitama Cancer Center, Chief Rewacher, 研究室・主任研究員 (60144862)
佐々木 恵美 藤田保健衛生大学, 医学部, 助手 (20178635)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥39,900,000 (Direct Cost: ¥39,900,000)
Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2001: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2000: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Keywords | estrogen / aromatase / steroid sulfatase / CVP IB 1 / estrogen sulfotransferase / fluorescent probe / breast cancer / aromatase knockout mice / エストロゲン依存性癌 / 細胞間相互作用 / ナロマターゼ / GFP / siRNA / OAT-3 / 炎症性サイトカイン / トランスジェニックマウス / Cyp1B1 / ホルモン療法 / 17β-水酸化ステロイド脱水素酵素 / 発癌感受性 / ノックアウトマウス / SNP / 組織特異的発現 |
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| Research Abstract |
The estrogen dynamics in breast cancer tissues, correllation of clinicopathological and prognostic factors with expression levels of 9 kinds of estrogen-related enzymes participating in the estrogen synthesis and estrogen-signal transducing system, was examined. High level expression of ErbB2, aromatase, and steroid sulfatase was a good prognostic factor, whereas that of ER-alfa and cyclin D2 was a poor prognostic factor. Next, in vivo carcinogenesis by estrogens was examined. DMBA of a chemical carcinogen caused rare tumorigenesis in aromataes-knockout mice (estrogen deficeint mice), in contrast with high frequency in wild mice. Furthermore, it was often observed in cyplBl-transgenic mice to estrogen-dependently suffered from tumors, suggesting that estrogens were metabolized to active carcinogens by cyp1B1. To analyze relationship between cancer cells-stromal cells interaction in the cancer tissues and clinicopathological factors, MCF7 cells carrying ERE-GFP was prepared and used for tracing ER activation in the cancer cells through the interaction by a means of a fluorescent GFP probe. The results indicated that GFP expression vary among stromal cells from breast cancer tissues and were more frequently induced in the postmenopausal tissues than in premenopausal ones. Sensitivities to aromatase inhibitors was also varied among the individual cases. Finally, correlation of estrogens dynamics in the cancer cells with proliferative capability and sensitivities of cancer cells to aromatase inhibitors was analyzed using stable transformant MCF7 cells with various profiles of estrogen metabolism. Consequently, it was indicated that indirect synthesis of estrogens from estrogen sufates by steroid sulfatase also plays an important role in the supply of estrogens to cancer cells as well as direct synthesis from androogens by aromatase, and suggested a possibility of steroid sulfatase inhibitors and estrogen sulfotransferase inducers as anti-cancer drugs.
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