Hormone-dependent cancer and the transcriptional coactivator MED1

• Project/Area Number: 18K15418
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kobe University
• Principal Investigator: HASEGAWA NATSUMI 神戸大学, 保健学研究科, 助教 (20708599)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 転写メディエーター / MED1 / 乳癌 / ホルモン依存性癌 / ERα / エストロゲン受容体 / MED１ / 転写コアクチベーター

Outline of Final Research Achievements

We have previously shown that Mediator subunit MED1 acts as a specific coactivator of ERα and is involved in the proliferation of pubertal mammary epithelial cells and ERα-positive breast cancer cells.
In order to determine the role for MED1 in the property of breast carcinomas, prognosis, response to therapy, and therapeutic resistance, we have prepared mouse models of mammary tumorigenesis harboring mutation of MED1. MED1 mutant mice lacking the nuclear receptor binding motifs had delayed tumor onset and changed localization of ERα. We proposed a new molecular mechanism by which the nuclear receptor-binding ability of MED1 contributes to growth of ERα-positive breast cancer cells.

Academic Significance and Societal Importance of the Research Achievements

乳癌の約80%はERαを発現し、タモキシフェン等の抗エストロゲン製剤は臨床で広く使用されているが、MED1はそのシグナル伝達を担うことから治療抵抗性にも関与する。本研究ではMED1がERαの核局在化を調節することにより、MED1の核内受容体結合能力がERα陽性乳癌細胞の増殖に関与する新しい分子メカニズムを提案した。本研究の先に、MED1を標的とする治療アプローチがありうることを示すものであり、今後の研究の動向に期待したい。

Research Products

• [Journal Article] Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4 (2020)
  • Author(s): Kana Kuronuma, Aya Yokoi, Tomoya Fukuoka, Muneaki Miyata, Akio Maekawa, Satowa Tanaka, Leo Matsubara, Chie Goto, Miki Matsuo, Hao-Wei Han, Mai Tsuruta, Haruka Murata, Hikari Okamoto, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito
  • Journal Title: Heliyon Volume: 6 Issue: 4 Pages: 03743-03743
  • DOI: 10.1016/j.heliyon.2020.e03743
  • NAID: 120006844969
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PML-RARα Induces All-Trans Retinoic Acid-Dependent Transcriptional Activation Through Interaction With MED1 (2019)
  • Author(s): Tomoya Fukuoka, Asami Kawai, Taku Takahara, Mahiro Mori, Robert G Roeder, Natsumi Hasegawa, Mitsuhiro Ito
  • Journal Title: Transcription Volume: 10 Issue: 3 Pages: 147-156
  • DOI: 10.1080/21541264.2019.1624467
  • NAID: 120006653243
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Translin restricts the growth of pubertal mammary epithelial cells estrogen-independently in mice. (2019)
  • Author(s): Matsubara L, Fukuoka T, Sudo K, Fukunaga T, Imanishi A, Kuronuma K, Matsuo M, Kamoshida S, Hasegawa N, Asano S, Ito M.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 521 Issue: 3 Pages: 562-568
  • DOI: 10.1016/j.bbrc.2019.10.176
  • NAID: 120006784500
  • Peer Reviewed / Int'l Joint Research
• [Presentation] MED1の核内受容体結合能に依存する乳癌増殖機構 (2022)
  • Author(s): 大橋侑加
  • Organizer: 第46回日本分子生物学会
• [Presentation] 転写メディエーターのサブユニットMED1によるエストロゲン受容体αの乳癌細胞核への局在 (2021)
  • Author(s): 金田直也
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] メディエーターのMED1サブユニットは内臓脂肪組織の2型自然免疫を制限する (2021)
  • Author(s): 藤原彩夏
  • Organizer: 第44回日本分子生物学会年会 https://www2.aeplan.co.jp/mbsj2021
• [Presentation] GATA1とメディエーターの多面的結合: GATA1による転写活性化モデル (2021)
  • Author(s): 安井樺風
  • Organizer: 第44回日本分子生物学会年会 https://www2.aeplan.co.jp/mbsj2021
• [Presentation] The interaction of PML-RARα with MED1 initiates ATRA dependent transcriptional activation. (2019)
  • Author(s): Tomoya Fukuoka，Miki Matsuo，Hikaru Tsutsumi，Mana Morikawa， Rino Kishida，Manami Tsuji，Kyo Saiki，Naoya Kanada， Mizuha Anamoto，Natsumi Hasegawa，Mitsuhiro Ito.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] MGP supports niche-dependent myeloid leukemic cells in a Glu γ-carboxylation independent manner. (2019)
  • Author(s): Haruka Murata，Kana Kuronuma，Leo Matsubara，Aya Yokoi， Hikari Okamoto，Mai Tsuruta，Tomoya Fukuoka，Miki Matsuo, Natsumi Hasegawa，Shigetaka Asano，Mitsuhiro Ito.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] ATRA dependent interaction of MED1 with oncofusion protein PML-RARα initiates transcriptional activation. (2019)
  • Author(s): Tomoya Fukuoka, Miki Matsuo, Hikaru Tsutsumi, Rino Kishida, Manami Tsuji, Mana Morikawa, Mizuha Anamoto, Naoya Kanada, Kyo Saiki, Robert G. Roeder, Natsumi Hasegawa, Mitsuhiro Ito.
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Matrix Gla protein is a niche factor that supports myeloid leukemic cells without Glu γ-carboxylation. (2019)
  • Author(s): Mai Tsuruta, Kana Kuronuma, Leo Matsubara, Haruka Murata, Hikari Okamoto, Hao-Wei Han, Tomoya Fukuoka, Miki Matsuo, Shun Ito, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito.
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Translin modulates mesenchymal cell proliferation and differentiation in mice. (2019)
  • Author(s): Kana Kuronuma, Yukiko Ikeuchi, Azusa Imanishi, Katsuko Sudo, Takako Fukunaga, Leo Matsubara, Aya Yokoi, Chie Goto, Tomoya Fukuoka, Miki Matsuo, Ruri Kono, Natsumi Hasegawa, Shigetaka Asano, Mitsuhiro Ito.
  • Organizer: 第42回日本分子生物学会年会