Study of the mechanism underlying the acquired hormone therapy resistance in breast cancer

• Project/Area Number: 20H03748
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Ohta Tomohiko 聖マリアンナ医科大学, 医学研究科, 教授 (60233136)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 乳がん / 子宮内膜がん / KDM4B / Fbxo22 / エストロゲン / DNA修復 / DNA損傷 / AKT / 内分泌療法 / ER / HER2

Outline of Research at the Start

申請者らは、乳がんの内分泌療法感受性を制御するメカニズムとしてFbxo22による転写調節因子KDM4Bの分解がエストロゲンシグナルの停止およびエストロゲン受容体（ER）モジュレーター（SERM）のアンタゴニスト作用に必須で、Fbxo22陰性乳がんは内分泌療法抵抗性となり、予後不良であることを見出した。本研究ではこのメカニズムの異常がER経路とHER2/PI3K経路のクロストークのキーイベントであることを証明し、HER2/PI3K経路が活性化したLuminal乳がんに対する内分泌療法感受性マーカーおよび治療薬を開発するための基盤とする。

Outline of Final Research Achievements

We investigated the role of the regulation of lysin demethylase KDM4B by ubiquitin ligase Fbxo22 on the carcinogenesis and the treatment of breast and endometrial cancers and found the following issues. Phosphorylation of KDM4B by AKT protected KDM4B from Fbxo22-mediated ubiquitination and prolonged KDM4B-mediated estrogen signaling. Phosphorylation of KDM4B by kinase X was critical for the retention of KDM4B at DNA double-strand breaks, and the DNA repair failure caused by inhibitors of kinase X renders synthetic lethality for cells with homologous recombination deficiency. All the mice with endometrial epithelium-specific knockout of Fbxo22 exhibited atypical endometrial hyperplasia or endometrial cancer, whereas wild-type mice treated with tamoxifen only developed hyperplasia.

Academic Significance and Societal Importance of the Research Achievements

AKTによるKDM4Bのリン酸化がKDM4Bを介したエストロゲンシグナルを助長することはLuminal/HER2乳がんが内分泌療法に抵抗を示す機序として臨床的に非常に重要である。キナーゼX阻害剤が、相同組換え修復不全を有するがんの治療薬として有望である可能性が示唆された。Fbxo22欠失により、タモキシフェン投与や、E2が低下する発情後期においてもエストロゲンシグナルが継続して子宮内膜上皮の増殖を誘導して発がんすることは、乳がんタモキシフェン治療における合併症としての子宮内膜発がん発症のメカニズム解明に向けたモデルとして重要である。

Research Products

• [Journal Article] The ZZ domain of HERC2 is a receptor of arginylated substrates (2022)
  • Author(s): Tencer AH, Liu J, Zhu J, Burkholder NT, Zhang Y, Wu W, Strahl BD, Ohta T, Kutateladze TG.
  • Journal Title: Sci Rep. Volume: 12 Issue: 1 Pages: 6063-6063
  • DOI: 10.1038/s41598-022-10119-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance (2022)
  • Author(s): Zhu Jing、Wu Wenwen、Togashi Yukiko、Taira Nihira Naoe、Johmura Yoshikazu、Zhu Dajiang、Nakanishi Makoto、Miyoshi Yasuo、Ohta Tomohiko
  • Journal Title: Breast Cancer Volume: 29 Issue: 6 Pages: 1076-1087
  • DOI: 10.1007/s12282-022-01389-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lack of impact of the <scp>ALDH2</scp> rs671 variant on breast cancer development in Japanese <scp>BRCA1</scp> /2‐mutation carriers (2022)
  • Author(s): Mori Tomoharu、Takata Minoru et al.
  • Journal Title: Cancer Medicine Volume: 12 Issue: 6 Pages: 6594-6602
  • DOI: 10.1002/cam4.5430
  • Peer Reviewed / Open Access
• [Journal Article] Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast (2021)
  • Author(s): Satoi Nagasawa, Yuta Kuze, Ichiro Maeda, Yasuyuki Kojima, Ai Motoyoshi, Tatsuya Onishi, Hibiki Seino, Ayako Suzuki, Masahide Seki, Eisuke Inoue, Koichiro Tsugawa, Tomohiko Ohta, Yutaka Suzuki, et al.
  • Journal Title: Communications Biology Volume: 4 Issue: 1
  • DOI: 10.1038/s42003-021-01959-9
  • Peer Reviewed / Open Access
• [Journal Article] Molecular targeted drugs resistance impairs double-strand break repair and sensitizes ER-positive breast cancer to PARP inhibitors (2021)
  • Author(s): Suzuki Y, Wu W, Ohta T, Hayashi S
  • Journal Title: Breast Cancer. Volume: 29 Issue: 1 Pages: 77-91
  • DOI: 10.1007/s12282-021-01282-5
  • Peer Reviewed / Open Access
• [Journal Article] RNF168 E3 ligase participates in ubiquitin signaling and recruitment of SLX4 during DNA crosslink repair (2021)
  • Author(s): Katsuki Yoko、Abe Masako、Park Seon Young、Wu Wenwen、Yabe Hiromasa、Yabe Miharu、van Attikum Haico、Nakada Shinichiro、Ohta Tomohiko、Seidman Michael M.、Kim Yonghwan、Takata Minoru
  • Journal Title: Cell Reports Volume: 37 Issue: 4 Pages: 109879-109879
  • DOI: 10.1016/j.celrep.2021.109879
  • NAID: 120007165816
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HERC2 inactivation abrogates nucleolar localization of RecQ helicases BLM and WRN (2021)
  • Author(s): Zhu M, Wu W, Togashi Y, Liang W, Miyoshi Y, Ohta T
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 360-360
  • DOI: 10.1038/s41598-020-79715-y
  • Peer Reviewed / Open Access
• [Journal Article] TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis (2021)
  • Author(s): Suzuki Narumi、Johmura Yoshikazu、Wang Teh-Wei、Migita Toshiro、Wu Wenwen、Noguchi Rei、Yamaguchi Kiyoshi、Furukawa Yoichi、Nakamura Shuhei、Miyoshi Ichiro、Yoshimori Tamotsu、Ohta Tomohiko、Nakanishi Makoto
  • Journal Title: Autophagy Volume: 11 Issue: 11 Pages: 1-18
  • DOI: 10.1080/15548627.2021.1897961
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FBXO22, an epigenetic multiplayer coordinating senescence, hormone signaling, and metastasis (2020)
  • Author(s): Johmura Yoshikazu、Harris Alexander S.、Ohta Tomohiko、Nakanishi Makoto
  • Journal Title: Cancer Science Volume: 111 Issue: 8 Pages: 2718-2725
  • DOI: 10.1111/cas.14534
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Does Trop-2 expression really not matter for the sensitivity to sacituzumab govitecan? (2023)
  • Author(s): Tomohiko Ohta
  • Organizer: Best of San Antonio Breast Cancer Symposium (SABCS) 2022 in Kyoto
  • Int'l Joint Research / Invited
• [Presentation] 乳がんの臨床を左右する新規エピジェネティックメカニズム (2021)
  • Author(s): 太田智彦
  • Organizer: 第29回日本乳癌学会学術総会
• [Presentation] ER陽性乳癌細胞における、薬剤耐性獲得に伴うDNA修復機構異常とPARP阻害薬感受性 (2021)
  • Author(s): 鈴木友菜, 豊澤大地, 呉文文, 太田智彦, 林慎一
  • Organizer: 第29回日本乳癌学会学術総会
• [Presentation] BRCA1 N末端の変異とPARP阻害剤感受性: E3リガーゼ活性についての再考 (2021)
  • Author(s): 太田智彦
  • Organizer: 第18回日本臨床腫瘍学会学術集会
• [Presentation] DNA修復脆弱性を標的としたがん治療 (2020)
  • Author(s): 太田智彦
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] エストロゲン受容体の発現を制御するFbxo22は浸潤性小葉癌の予後因子となりうるか (2020)
  • Author(s): 中川紗紀, 宮下穣, 江幡明子, 佐藤章子, 原田成美, 濱中洋平, 甘利正和, 平川久, 大井恭代, 太田智彦, 多田寛, 石田孝宣
  • Organizer: 第28回日本乳癌学会学術総会
• [Presentation] CDK4/6阻害薬耐性細胞はDNA修復機構に異常をきたしPARP阻害薬に反応する (2020)
  • Author(s): 鈴木友菜, 豊澤大地, 呉文文, 丹羽俊文, 太田智彦, 林慎一
  • Organizer: 第28回日本乳癌学会学術総会
• [Book] 乳癌診療 state of the art - 科学に基づく最新診療「遺伝性乳癌に対する遺伝子修復不全標的治療」 (2022)
  • Author(s): 太田智彦
  • Total Pages: 5
  • Publisher: 医歯薬出版株式会社
• [Book] Hereditary Breast and Ovarian Cancer「Molecular Basis of BRCA1 and BRCA2: Homologous Recombination Deficiency and Tissue-Specific Carcinogenesis」 (2021)
  • Author(s): Ohta T, Wu W
  • Total Pages: 15
  • Publisher: Springer
• [Book] 乳腺腫瘍学「7. BRCA変異診断、ゲノム診断」 (2020)
  • Author(s): 太田智彦
  • Total Pages: 4
  • Publisher: 金原出版
• [Book] 医学のあゆみ「BRCA遺伝子変異による臓器特異的な発がん」 (2020)
  • Author(s): 郷田敦史, 呉文文, 太田智彦
  • Total Pages: 5
  • Publisher: 医歯薬出版
• [Remarks] 聖マリアンナ医科大学大学院 医学研究科 応用分子腫瘍学
  • URL: http://www.marianna-u.ac.jp/t-oncology/index.html