Modification of estrogen action of breast cancer by tumor-associated immune cells

• Project/Area Number: 26860229
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Tohoku University
• Principal Investigator: TAKAGI Kiyoshi 東北大学, 医学(系)研究科(研究院), 助教 (80595562)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 乳癌 / マクロファージ / 腫瘍免疫

Outline of Final Research Achievements

Immunohistochemical analysis revealed that infiltrating macrophages were associated with more aggresive phenotype of estrogen receptor-positive breast carcinomas. Generally, macrophages are divided into M1 and M2 macrophages based on molecular markers, and most of intratumoral macrophages are M2. Coculture of MCF-7 breast caancer cells and M2-polarized THP-1 and U937 leukemic cells demonstrated that M2 macrophages enhanced migration property of breast cancer cells, while expression of estrogern recetor and estrogen-responsive genes was down-reglated in breast cancer cells.
These fndings may suggest taht breast cancer cells acquires more aggressive phenotype by interaction with M2macrophages, and lose estrogen-dependency. Therfore, it is speculated that M2 macrophages are possibly asspciated with resistance to endocrine therapy of estrogen-sensitive breast cancer and therefore M2 macrophages are considered potent therapeutic target of breast carcinomas.

Research Products

• [Journal Article] Nucleobindin 2 (NUCB2) in human endometrial carcinoma: a potent prognostic factor associated with cell proliferation and migration (2016)
  • Author(s): Takagi K, Miki Y, Tanaka S, Hashimoto C, Watanabe M, Sasano H, Ito K, Suzuki T
  • Journal Title: Endocrine Journal Volume: 63 Issue: 3 Pages: 287-299
  • DOI: 10.1507/endocrj.EJ15-0490
  • NAID: 130005140784
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KLF15 in breast cancer: a novel tumor suppressor? (2015)
  • Author(s): Yoda T, McNamara KM, Miki Y, Onodera Y, Takagi K, Nakamura Y, Ishida T, Suzuki T, Ohuchi N, Sasano H.
  • Journal Title: Cell Oncol (Dordr). Volume: 38（3） Issue: 3 Pages: 227-235
  • DOI: 10.1007/s13402-015-0226-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 11β-Prostaglandin F2α, a bioactive metabolite catalyzed by AKR1C3, stimulates Prostaglandin F receptor and induces Slug expression in breast cancer. (2015)
  • Author(s): Yoda T, Kikuchi K, Miki Y, Onodera Y, Hata S, Takagi K, Nakamura Y, Hirakawa H, Ishida T, Suzuki T, Ohuchi N, Sasano H, McNamara KM.
  • Journal Title: Mol Cell Endocrinol. Volume: 413 Pages: 236-247
  • DOI: 10.1016/j.mce.2015.07.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. (2015)
  • Author(s): Takayama K, Misawa A, Suzuki T, Takagi K, Hayashizaki Y, Fujimura T, Homma Y, Takahashi S, Urano T, Inoue S
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 8219-8219
  • DOI: 10.1038/ncomms9219
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Abnormal expression of miR-1 in breast carcinoma as a potent prognostic factor. (2015)
  • Author(s): Minemura H, Takagi K, Miki Y, Shibahara Y, Nakagawa S, Ebata A, Watanabe M, Ishida T, Sasano H, Suzuki T.
  • Journal Title: Cancer Sci. Volume: 106(11) Issue: 11 Pages: 1642-1650
  • DOI: 10.1111/cas.12808
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunolocalization of thymidylate synthase as a favorable prognostic marker in estrogen receptor-positive breast carcinoma (2015)
  • Author(s): Kiyoshi Takagi, Yasuhiro Miki, Yasuhiro Nakamura, Hisashi Hirakawa, Yoichiro Kakugawa, Goro Amano, Mika Watanabe, Takanori Ishida, Hironobu Sasano and Takashi Suzuki
  • Journal Title: HISTOLOGY AND HISTOPATHOLOGY Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The role of 5α-reductase type 1 associated with intratumoral dihydrotestosterone concentrations in human endometrial carcinoma. (2015)
  • Author(s): Tanaka S, Miki Y, Hashimoto C, Takagi K, Doe Z, Li B, Yaegashi N, Suzuki T, Ito K.
  • Journal Title: Mol Cell Endocrinol. Volume: 401 Pages: 56-64
  • DOI: 10.1016/j.mce.2014.11.022
  • Peer Reviewed
• [Journal Article] Identification of myelin transcription factor 1 (MyT1) as a subunit of the neural cell type-specific lysine-specific demethylase 1 (LSD1) complex. (2014)
  • Author(s): Yokoyama A, Igarashi K, Sato T, Takagi K, Otsuka I M, Shishido Y, Baba T, Ito R, Kanno J, Ohkawa Y, Morohashi K, Sugawara A.
  • Journal Title: J Biol Chem. Volume: 289 Issue: 26 Pages: 18152-18162
  • DOI: 10.1074/jbc.m114.566448
  • Peer Reviewed
• [Journal Article] Immunolocalization of corticotropin-releasing hormone (CRH) and its receptors (CRHR1 and CRHR2) in human endometrial carcinoma: CRHR1 as a potent prognostic factor. (2014)
  • Author(s): Sato N, Takagi K, Suzuki T, Miki Y, Tanaka S, Nagase S, Warita H, Fukudo S, Sato F, Sasano H, Ito K.
  • Journal Title: Int J Gynecol Cancer Volume: 24 Issue: 9 Pages: 1549-1557
  • DOI: 10.1097/igc.0000000000000269
  • Peer Reviewed / Open Access
• [Presentation] 膵癌組織におけるCRH発現と生存予後の関連 (2015)
  • Author(s): 佐藤菜保子、片寄友、川口桂、大塚英郎、森川孝則、中川圭、元井冬彦、内藤剛、高木清司、鈴木貴、福土審、佐藤冨美子、海野倫明
  • Organizer: 第53回 日本癌治療学会誌
  • Place of Presentation: 京都（国立京都国際会館）
  • Year and Date: 2015-10-29
• [Presentation] Hexokinase II in human colorectal cancer as a potent prognostic predictor (2015)
  • Author(s): 片桐宗利、鈴木貴、唐澤秀明、高木清司、前田晋平、元井冬彦、内藤剛、海野倫明
  • Organizer: 第74回 日本癌学会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] Effects of relaxin on endometrial cancer cell proliferation and invasion through differential pathways (2015)
  • Author(s): 笛未崎、三木康宏、高木清司、鈴木貴、伊藤潔
  • Organizer: 第74回 日本癌学会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] Involvement of stress hormone, cortisol in endometrial cancer progression (2015)
  • Author(s): 三木康宏、笛未崎、高木清司、鈴木貴、笹野公伸、伊藤潔
  • Organizer: 第74回 日本癌学会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] Abnormal expression of miR-1 in breast carcinoma as apotent prognostic factor (2015)
  • Author(s): 峯村洋行、高木清司、三木康宏、柴原裕紀子、中川紗紀、江幡明子、渡辺みか、石田孝宣、笹野公伸、鈴木貴
  • Organizer: 第74回 日本癌学会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] Immunolocalization of CITED2 in human breast carcinoma: a potent prognostic factor (2015)
  • Author(s): 高木清司、峯村洋行、三木康宏、高橋光、中村保宏、石田孝宣、笹野公伸、鈴木貴
  • Organizer: 第74回 日本癌学会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] 乳癌微小環境における癌と脂肪細胞の相互作用に関与するLCN2の役割 (2015)
  • Author(s): 櫻井美奈子、河原由依、三木康宏、高木清司、鈴木貴、石田孝宜、大内憲明、笹野公伸
  • Organizer: 第88回 日本内分泌学会
  • Place of Presentation: 東京（ホテルニューオータニ東京）
  • Year and Date: 2015-04-23
• [Presentation] S100A7 in breast carcinoma invasion into adipose tissue (2014)
  • Author(s): Minako Sakurai, Yasuhiro Miki, Kiyoshi Takagi, Takashi Suzuki, Hironobu Sasano
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 11β-prostaglandin F2α produced by AKR1C3 stimulates FP-receptor and contributes to breast cancer progression (2014)
  • Author(s): Tomomi Yoda, Keely MMcNamara, Yasuhiro Miki, Kiyoshi Takagi, Takashi Suzuki, Hironobu Sasano
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Transforming acidic coiled-coil-containing protein 2 (Tacc2) immunolocalization in breast carcinoma (2014)
  • Author(s): Yoshiaki Onodera, Kiyoshi Takagi, Yasuhiro Miki, Yasuhiro Nakamura, Mika Watanabe, Takanori Ishida, Hironobu Sasano, Satoshi Inoue, Takashi Suzuki
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] NUCB2 in human endometrial carcinoma as a potent prognostic factor (2014)
  • Author(s): Kiyoshi Takagi, Yasuhiro Miki, Sota Tanaka, Nobuo Yaegashi, Hironobu Sasano, Kiyoshi Ito, Takashi Suzuki
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] p62/sequestosome 1 is asn independent prognostic factor and promotes cell proliferation in human colorectal carcinoma (2014)
  • Author(s): Shun Nakayama, Takashi Suzuki, Shinichi Yabuuchi, Kiyoshi Takagi, Yoshiaki Onodera, Yasuhiro Nakamura, Mika Watanabe, Hiroshi Yoshida, Takanori Morikawa, Hideaki Karasawa, Takeshi Naito, Michiaki Unno, Hironobu Sasano
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Tumor suppressive roles of ARHGAP15 in human breast cancer (2014)
  • Author(s): Kiyoshi Takagi, Yasuhiro Miki, Yoshiaki Onodera, Yasuhiro Nakamura, Takanori Ishida, Hironobu Sasano and Takashi Suzuki
  • Organizer: ICE/ENDO 2014
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] 11β-Prostaglangin F2α Produced By AKP1C3 Stimulates FP-Receptor and Contributes to Breast Cancer Progression (2014)
  • Author(s): Tomomi Yoda, Keely MMcNamara, Yasuhiro Miki, Kiyoshi Takagi, Takanori Ishida, Takashi Suzuki, Noriaki Ohuchi, Hironobu Sasano
  • Organizer: ICE/ENDO 2014
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] Identification of Signaling Factors Involved in an Interaction Between Human Breast Carcinoma and Adipocytes (2014)
  • Author(s): Minako Sakurai, Yasuhiro Miki, Kiyoshi Takagi, Takashi Suzuki, Hironobu Sasano
  • Organizer: ICE/ENDO 2014
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2014-06-21 – 2014-06-24
• [Presentation] Intratumoral Concentration of Stress Hormone, Cortisol in Endometrial Carcinoma (2014)
  • Author(s): Yasuhiro Miki, Kiyoshi Takagi, Zhulanqiqige Doe, Sota Tanaka, Takashi Suzuki, Hironobu Sasano, Kiyoshi Ito
  • Organizer: ICE/ENDO 2014
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2014-06-21 – 2014-06-24
• [Book] 医学のあゆみ (2015)
  • Author(s): 鈴木貴、高木清司
  • Total Pages: 2
  • Publisher: 医歯薬出版