| Project/Area Number |
18592031
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Matsumoto Dental University |
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Principal Investigator |
HIRAGA Toru Matsumoto Dental University, School of Dentistry, Associate Professor (70322170)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Hiroaki Matsumoto Dental University, School of Dentistry, Professor (50227930)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,880,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Breast Cancer / Bone Metastasis / Hynoxia / HIF-1 |
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| Research Abstract |
In this study, we investigated the effects of hypoxia and the transcription factor hypoxia-inducible factor-1α (HT-la) on the development and progression of bone metastases of breast cancer.
1. Localization of Hypoxic Regions and Expression of HIF-1α in Bone Metastases of Breast Cancer
In a mouse model of bone metastasis using human breast cancer cells, we found hypoxic regions in the tumor nests colonized in bone. Immunohistochemical studies also revealed the expression of HIF-1α associated with hypoxia.
2. Effects of Hypoxia on Bone Metastases of Breast Cancer
(1) TAT-ODD-Procaspase3 (TOP3) We developed the unique fusion protein TOP3, which specifically induces apoptosis in hypoxic cells. We confirmed that TOP3 specifically induced apoptosis in breast cancer cells under hypoxia in vitro. Furthermore, TOP3 suppressed the development of bone metastases of breast cancer in nude mice.
(2) Effects of Hypoxia on Osteoblasts and Osteoclasts Hypoxia markedly inhibited osteoblastic differentiation
… More
in vitro. In contrast, osteoclast differentiation was significantly stimulated by hypoxia.
3. Effects of HIF-1α on Bone Metastases of Breast Cancer
(1) Induction of HIF-1α in Breast Cancer Cells We confirmed that hypoxia induced the accumulation of HT-1α in breast cancer cells in vitro.
(2) Breast Cancer Cells Overexpressing Constitutively-Active and Dominant-Negative Forms of HT-1α We established breast cancer cells stably transfected with constitutively-active and dominant-negative forms of HT-1α (CA-HT-1α and DN-HT-1α, respectively). We then examined the capacity of these clones to develop bone metastases in nude mice. CA-HT-1α increased the development of bone metastases. On the other hand, DN-HT-1α significantly reduced the bone metastases.
In conclusion, these results suggest that tumor-associated hypoxia and HIF-1α expression promote the progression of bone metastases in breast cancer. Our results also suggest that hypoxia and HIF-1α lead to the development of osteolytic bone metastases by suppressing osteoblast differentiation and promoting osteoclastogenesis. Less
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