| 研究課題/領域番号 |
24710066
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| 研究機関 | 独立行政法人放射線医学総合研究所 |
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研究代表者 |
GUILLAUME Vares 独立行政法人放射線医学総合研究所, 放射線防護研究センター, 研究員 (10415432)
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| 研究期間 (年度) |
2012-04-01 – 2016-03-31
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| キーワード | Cancer stem cells / Breast cancer / Progesterone / Radiation / miRNA |
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| 研究実績の概要 |
We wanted to assess whether the modulation of radiation-induced breast cancer risk by steroid hormones could involve cancer stem cells (CSCs). In agreement with this hypothesis, we could observe the generation of breast CSCs by ionizing radiation and exposure to steroid hormones. Results were published in two peer-reviewed papers and presented at international conferences.
First, we observed that progesterone stimulated the expansion of the CSC compartment both in progesterone receptor (PR)-positive breast cancer cells and in PR-negative normal cells. In MCF10A normal epithelial basal-like PR-negative cells, progesterone-treatment and irradiation triggered cancer and stemness-associated microRNA regulations (such as the downregulation of miR-22 and miR-29c expression), which resulted in increased proportions of radiation-resistant tumor-initiating CSCs (Vares et al., 2013).
We then discovered that in MCF10A cells, progesterone activated the PI3k/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the PI3k/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of PI3K/Akt via mPR resulted in the inactivation of FOXO transcriptional activity, the upregulation of snail and slug expression and a downregulation of miR-29 expression, which led to increased levels of KLF4, a transcription factor required for breast CSC maintenance. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs (Vares et al., 2015).
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Our initial research project is now completed. We have successfully validated our hypothesis and we have described a new PR-independent pathway in MCF10A basal-like breast cells, which involves the activation of mPR by progesterone. Results were published in two peer-reviewed papers (Vares et al. 2013, PloS one IF 3.5; Vares et al. 2015, Cancer Letters IF 5.0) and presented at international (International Society for Stem Cell Research ISSCR, American Association for Cancer Research AACR) and domestic (Japan Cancer Association JCA) conferences.
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| 今後の研究の推進方策 |
We would now like to expand these findings and describe mechanisms responsible for CSC initiation and maintenance in basal-like breast cancer and other challenging cancer models. Based on these new data, we will devise potential anti-CSC strategies targeting signaling pathways and miRNAs associated with CSC initiation, maintenance and resistance to radiation/chemotherapy. To attain this goal, we started a new collaborative project involving three research groups in Japan and Europe.
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| 次年度使用額が生じた理由 |
I have found out a new molecular pathway in CSC initiation and published those findings.
Therefore, it is necessary to improve the previous plan and perform additional experiments.
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| 次年度使用額の使用計画 |
In April 2014, JPY1,170,000 were transferred (including JPY270,000 indirect cost).
In April 2015, JPY384,691 were remaining. I applied for an extension until May 2015, in order to attend the AACR (American Association for Cancer Research) meeting in Philadelphia, PA, and to perform additional experiments.
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