Involvement of the pioneer factor FoxA1 in breast cancer progression.

• Project/Area Number: 16K08227
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Chiba University
• Principal Investigator: Noritaka Yamaguchi 千葉大学, 大学院薬学研究院, 准教授 (80399469)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: シグナル伝達 / 癌

Outline of Final Research Achievements

FoxA1 is a pioneer factor that regulates chromatin remodeling and gene expression. FoxA1 is known to be involved in breast cancer progression through expression of genes controlling cell survival and growth. However, FoxA1 expression is reduced or lost in malignant types of breast cancer cells, and the relationship between the presence of FoxA1 expression and the malignancy of breast cancer cells has not been clarified. In this study, we found that loss of FoxA1 expression causes acquisition of chemo-resistance in breast cancer cells. This finding suggests that FoxA1 has both promotive and suppressive roles in breast cancer progression. Specific inhibition of its promotive roles in breast cancer progression is required for the treatment of breast cancer patients.

Academic Significance and Societal Importance of the Research Achievements

本研究により、クロマチン制御因子FoxA1が乳癌細胞の悪性化の促進と抑制の二面的な役割を持つことが明らかとなった。これまでの解析によってFoxA1が乳癌細胞の生存や増殖に寄与することが判明していたため、FoxA1の機能抑制が乳癌の治療に役立つと考えられてきたが、本研究によってFoxA1の機能抑制が薬剤抵抗性を誘導し乳癌の治療をより困難にする可能性が示された。今後、乳癌悪性化におけるFoxA1の促進的機能と抑制的機能について分子レベルの詳細な解析を進め、促進的機能のみを阻害する治療法開発を行う必要がある。

Research Products

• [Journal Article] Desuppression of TGF-β signaling via nuclear c-Abl-mediated phosphorylation of TIF1γ/TRIM33 at Tyr-524, -610, and -1048. (2019)
  • Author(s): Yuki R, Tatewaki T, Yamaguchi N, Aoyama K, Honda T, Kubota S, Morii M, Manabe I, Kuga T, Tomonaga T, Yamaguchi N
  • Journal Title: Oncogene Volume: 38 Issue: 5 Pages: 637-655
  • DOI: 10.1038/s41388-018-0481-z
  • Peer Reviewed
• [Journal Article] Role for tyrosine phosphorylation of SUV39H1 histone methyltransferase in enhanced trimethylation of histone H3K9 via neuregulin-1/ErbB4 nuclear signaling. (2019)
  • Author(s): Nakajo H, Ishibashi K, Aoyama K, Kubota S, Hasegawa H, Yamaguchi N, Yamaguchi N
  • Journal Title: Biochem Biophys Res Commun. Volume: 511 Issue: 4 Pages: 765-771
  • DOI: 10.1016/j.bbrc.2019.02.130
  • Peer Reviewed
• [Journal Article] Forkhead box protein A1 confers resistance to transforming growth factor‐β‐induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation (2018)
  • Author(s): Hirata Kensuke、Takakura Yuki、Shibazaki Misato、Morii Mariko、Honda Takuya、Oshima Motohiko、Aoyama Kazumasa、Iwama Atsushi、Nakayama Yuji、Takano Hiroyuki、Yamaguchi Naoto、Yamaguchi Noritaka
  • Journal Title: Journal of Cellular Biochemistry Volume: 120 Issue: 2 Pages: 2259-2270
  • DOI: 10.1002/jcb.27551
  • Peer Reviewed
• [Journal Article] Golgi Distribution of Lyn to Caveolin- and Giantin-Positive <i>cis</i>-Golgi Membranes and the Caveolin-Negative, TGN46-Positive <i>trans</i>-Golgi Network (2018)
  • Author(s): Okamoto A, Morinaga T, Yamaguchi N, Yamaguchi N
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 1 Pages: 142-146
  • DOI: 10.1248/bpb.b17-00681
  • NAID: 130006301302
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP). (2017)
  • Author(s): Kuki K, Yamaguchi N, Iwasawa S, Takakura Y, Aoyama K, Yuki R, Nakayama Y, Kuga T, Hashimoto Y, Tomonaga T, Yamaguchi N
  • Journal Title: Biochemical and biophysical research communications Volume: 490 Issue: 3 Pages: 1045-1051
  • DOI: 10.1016/j.bbrc.2017.06.163
  • Peer Reviewed / Open Access
• [Journal Article] FOXA1 Induces E-Cadherin Expression at the Protein Level <i>via</i> Suppression of Slug in Epithelial Breast Cancer Cells (2017)
  • Author(s): Anzai E, Hirata K, Shibazaki M, Yamada C, Morii M, Honda T, Yamaguchi N, Yamaguchi N
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 9 Pages: 1483-1489
  • DOI: 10.1248/bpb.b17-00307
  • NAID: 130006038770
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] The Truncated Isoform of the Receptor Tyrosine Kinase ALK Generated by Alternative Transcription Initiation (ALK^ATI) Induces Chromatin Structural Changes in the Nucleus in a Kinase Activity-Dependent Manner (2017)
  • Author(s): Takakura Y, Yamaguchi N, Honda T, Morii M, Yuki R, Nakayama Y, Yamaguchi N
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 11 Pages: 1968-1975
  • DOI: 10.1248/bpb.b17-00548
  • NAID: 130006191980
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] v-Src-driven transformation is due to chromosome abnormalities but not Src-mediated growth signaling. (2017)
  • Author(s): Honda T, Morii M, Nakayama Y, Suzuki K, Yamaguchi N, Yamaguchi N
  • Journal Title: Scientific reports Volume: 8 Issue: 1 Pages: 1063-1063
  • DOI: 10.1038/s41598-018-19599-1
  • Peer Reviewed / Open Access
• [Journal Article] Down-regulation of forkhead box protein A1 (FOXA1) leads to cancer-stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6. (2017)
  • Author(s): Noritaka Yamaguchi, Yuji Nakayama, and Naoto Yamaguchi.
  • Journal Title: Journal of Biological Chemistry Volume: 印刷中 Issue: 20 Pages: 8136-8148
  • DOI: 10.1074/jbc.m116.763276
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tyrosine Phosphorylation of the Pioneer Transcription Factor FoxA1 Promotes Activation of Estrogen Signaling. (2017)
  • Author(s): Noritaka Yamaguchi, Misato Shibazaki, Chiaki Yamada, Erina Anzai, Mariko Morii, Yuji Nakayama, Takahisa Kuga, Yuuki Hashimoto, Takeshi Tomonaga, and Naoto Yamaguchi.
  • Journal Title: Journal of Cellular Biochemistry Volume: 118 Issue: 6 Pages: 1453-1461
  • DOI: 10.1002/jcb.25804
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recruitment of Lyn from endomembranes to the plasma membrane through calcium-dependent cell-cell interactions upon polarization of inducible Lyn-expressing MDCK cells. (2017)
  • Author(s): Takao Morinaga, Sayuri Yanase, Aya Okamoto, Noritaka Yamaguchi, and Naoto Yamaguchi.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 493-493
  • DOI: 10.1038/s41598-017-00538-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Src acts as an effector for Ku70-dependent suppression of apoptosis through phosphorylation of Ku70 at Tyr-530 (2017)
  • Author(s): Morii, M., Kubota, S., Honda, T., Yuki, R., Morinaga, T., Kuga, T., Tomonaga, T., Yamaguchi, N.-t., and Yamaguchi, N.
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 5 Pages: 1648-1665
  • DOI: 10.1074/jbc.m116.753202
  • Peer Reviewed
• [Journal Article] Protective role for lipid modifications of Src-family kinases against chromosome missegregation (2016)
  • Author(s): Honda, T., Soeda, S., Tsuda, K., Yamaguchi, C., Aoyama, K., Morinaga, T., Yuki, R., Nakayama, Y., Yamaguchi, N.-t., and Yamaguchi, N.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 38751-38751
  • DOI: 10.1038/srep38751
  • Peer Reviewed / Open Access
• [Presentation] 上皮間葉転換と細胞内代謝リモデリングのクロストーク (2019)
  • Author(s): 山口憲孝, 山口直人, 高野博之.
  • Organizer: 第139回日本薬学会年会
  • Invited
• [Presentation] 転写共役因子VGLL3による上皮間葉転換の制御機構の解析 (2019)
  • Author(s): 高倉勇気, 杉野歩美, 岩澤脩斗, 平田健介, 岡田和之, 竹洞裕貴, 平井直人, 堀 直人, 町田萌香, 高野博之, 山口直人, 山口憲孝.
  • Organizer: 第139回日本薬学会年会
• [Presentation] 乳がん細胞のTGF-beta誘導性アポトーシスへの抵抗性に寄与する転写因子の解析 (2019)
  • Author(s): 平田健介, 山田千愛, 安斎絵里菜, 柴崎美里, 本田拓也, 森井真理子, 高野博之, 山口直人, 山口憲孝.
  • Organizer: 第139回日本薬学会年会
• [Presentation] Involvement of FOXA1 in resistance to TGF-beta-induced apoptosis in estrogen receptor-positive breast cancer cells. (2018)
  • Author(s): Yamaguchi, N, Takakura, Y., Hirata, K., Takano, H., and Yamaguchi, N.
  • Organizer: The 2018 ASCB/EMBO Meeting
  • Int'l Joint Research
• [Presentation] TGF-betaにより発現誘導される転写共役因子VGLL3によるEMT制御機構の解析. (2018)
  • Author(s): 山口憲孝
  • Organizer: 第91回日本生化学会大会
  • Invited
• [Presentation] ER陽性乳癌細胞におけるFOXA1によるTGF-beta誘導性細胞死の抑制機構の解析. (2018)
  • Author(s): 山口憲孝, 山口直人.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 乳癌細胞におけるTGF-beta誘導性細胞死の抑制機構の解析. (2018)
  • Author(s): 山口憲孝, 山口直人.
  • Organizer: 第138回日本薬学会年会
• [Presentation] The molecular mechanisms underlying resistance to TGF-beta-induced apoptosis in breast cancer cells. (2018)
  • Author(s): Noritaka Yamaguchi and Naoto Yamaguchi
  • Organizer: The 2nd International Conference on Genomic Medicine 2018
  • Int'l Joint Research / Invited
• [Presentation] エストロゲン依存性乳癌細胞のタモキシフェン耐性獲得におけるNF-κB経路の役割. (2017)
  • Author(s): 山口憲孝, 中山祐治, 山口直人.
  • Organizer: 第137回日本薬学会年会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-27
• [Presentation] 乳がん細胞におけるTGF-betaシグナルの阻害機構の解析. (2017)
  • Author(s): 平田健介, 山田千愛, 安斎絵里菜, 柴崎美里, 本田拓也, 森井真理子, 山口直人, 山口憲孝.
  • Organizer: 2017年度 生命科学系学会合同年次大会
• [Presentation] 乳がん細胞におけるTGF-betaシグナルの阻害因子による細胞死抑制機構の解析. (2017)
  • Author(s): 平田健介, 山田千愛, 安斎絵里菜, 柴崎美里, 本田拓也, 森井真理子, 山口直人, 山口憲孝.
  • Organizer: 第61回日本薬学会関東支部大会
• [Presentation] 乳がん細胞におけるTGF-betaシグナル伝達の阻害因子の解析. (2017)
  • Author(s): 平田健介, 山田千愛, 安斎絵里菜, 柴崎美里, 本田拓也, 森井真理子, 山口直人, 山口憲孝.
  • Organizer: 平成29年度日本生化学会関東支部例会
• [Presentation] エストロゲン依存性乳癌細胞のタモキシフェン耐性獲得機構の解析. (2016)
  • Author(s): 山口憲孝, 中山祐治, 山口直人.
  • Organizer: 山口憲孝, 中山祐治, 山口直人.
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30