Ligand-independent activation of estrogen receptor pathway in gynecologic malignancies

• Project/Area Number: 20591947
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kobe University
• Principal Investigator: SUDO Tamotsu Kobe University, 医学研究科, 医学研究員 (50397824)
• Co-Investigator(Kenkyū-buntansha): IGUCHI Taisen 大学共同利用機関法人自然科学研究機構(共通施設), 岡崎統合バイオサイエンスセンター, 教授 (90128588)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: エストロゲン / p21 activated kinase-1 / VAV1 / ジエチルスチベストロール / ジエチルスチルベストロール

Research Abstract

(1) PAK1, a major target of the small GTPases, growth factors and lipid signaling, regulates cell motility, hormone action, invasiveness, and survival, all of which are required for tumor development. We found phospho-PAK1 expression in 14% by immunohistochemical staining of ovarian cancer patients. Patients with phospho-PAK1 (+) in the tumor had poor survival compared with those with negative expression (P=0.02). Furthermore, PAK1 inhibition by PAK1 specific inhibitor (PAK18) greatly increased the sensitivity of phospho-PAK1 positive ovarian cancer cells to epirubicin.
(2) Vav1-positive tumors had a worse overall survival (P=0.0392) and progression free survival (P=0.0298) compared to Vav1-negative tumors in early-stage ovarian cancer patients. Significant down-regulation of E-cadherin was observed in SKOV-3-Vav1 versus control cells. Expression of VAV1 causally contributes to epithelial-mesenchymal transition and ovarian cancer progression through the suppression of E-cadherin.

Research Products

• [Journal Article] Relationship between ABCF2 expression and response to chemotherapy or prognosis in clear cell adenocarcinoma of the ovary. (2010)
  • Author(s): Tsuda H, Ito K, Yaegashi N, Hirasawa A, Sudo T, Kita T, Terai Y, Kigawa J, Sugiyama T, Aoki D.
  • Journal Title: Int J Gynecol Cancer. 20(5) Pages: 794-797
• [Journal Article] Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype. (2010)
  • Author(s): Kusanagi Y, Kojima A, Mikami Y, Kiyokawa T, Sudo T, Yamaguchi S, Nishimura R.
  • Journal Title: American Journal of Pathology.
• [Journal Article] The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423. (2010)
  • Author(s): Hashimoto H, Sudo T, Maruta H, Nishimura R.
  • Journal Title: Drug Discov Ther. 4(1) Pages: 1-4
• [Journal Article] Estrogen receptor ESR1 is indispensable for the induction of persistent vaginal change by neonatal 5alpha-dihydrotestosterone exposure in mice. (2010)
  • Author(s): Miyagawa S, Katsu Y, Ohta Y, Sudo T, Lubahn DB, Iguchi T.
  • Journal Title: Biol Reprod. 82(3) Pages: 497-503
• [Journal Article] Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. (2010)
  • Author(s): Kusanagi Y, Kojima A, Mikami Y, Kiyokawa T, Sudo T, Yamaguchi S, Nishimura R
  • Journal Title: American Journal of Pathology Volume: 177(5) Pages: 2169-2175
  • Peer Reviewed
• [Journal Article] Molecular cloning, characterization, and chromosome mapping of reptilian estrogen receptors. (2010)
  • Author(s): Katsu Y, Matsubara K, Kohno S, Matsuda Y, Toriba M, Oka K, Guillette LJ Jr, Ohta Y, Iguchi T.
  • Journal Title: Endocrinology Volume: 151(12) Pages: 5710-5720
  • Peer Reviewed
• [Journal Article] Relationship between ABCF2 expression and response to chemotherapy or prognosis in clear cell adenocarcinoma of the ovary. (2010)
  • Author(s): Tsuda H, Ito K, Yaegashi N, Hirasawa A, Sudo T, Kita T, Terai Y, Kigawa J, Suglyama T, Aoki D.
  • Journal Title: International Journal of Gynecologic Cancer Volume: 20(5) Pages: 794-777
  • Peer Reviewed
• [Journal Article] Estrogen Receptor ESR1 Is Indispensable for the Induction of Persistent Vaginal Change by Neonatal 5alpha-Dihydrotestosterone Exposure in Mice (2010)
  • Author(s): Shinichi Miyagawa, Tamotsu Sudo, Taisen Iguchi
  • Journal Title: BIOLOGY OF REPRODUCTION 82 Pages: 497-503
  • Peer Reviewed
• [Journal Article] The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of humsn ovarian cancer cell lines in which PAK1 is abnormally activated by autophosp horylation at Thr 423. (2010)
  • Author(s): Hashimoto H, Sudo T, Maruta H, Nishimura R
  • Journal Title: Drug Discoveries & Therapeutics 4(1) Pages: 1-4
  • Peer Reviewed
• [Journal Article] Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells. (2009)
  • Author(s): Nakayama S, Torikoshi Y, Takahashi T, Yoshida T, Sudo T, Matsushima T, Kawasaki Y, Katayama A, Gohda K, Hortobagyi GN, Noguchi S, Sakai T, Ishihara H, Ueno NT.
  • Journal Title: Breast Cancer Res. 11(1)
• [Journal Article] From reptilian phylogenomics to reptilian genomes : analyses of c-Jun and DJ-1 proto-oncogenes. (2009)
  • Author(s): Katsu Y, Braun EL, Guillette LJ Jr, Iguchi T.
  • Journal Title: Cytogenet Genome Res. 127(2-4) Pages: 79-93
• [Journal Article] Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells. (2009)
  • Author(s): Nakayama S, Sudo T, Ueno NT
  • Journal Title: Breast Cancer Res 11(1)
  • Peer Reviewed
• [Journal Article] Effects of diethylstilbestrol on ovarian follicle development in neonatal mice. (2009)
  • Author(s): Kim, H., Iguchi, T., Sato, T
  • Journal Title: Reprod. Toxicol 27 Pages: 55-62
  • Peer Reviewed
• [Journal Article] Germ cell specific protein VASA is over-expressed in epithelial ovarian cancer and disrupts DNA damage-induced G2 checkpoint. (2008)
  • Author(s): Hashimoto H, Sudo T, Mikami Y, Otani M, Takano M, Tsuda H, Itamochi H, Katabuchi H, Ito M, Nishimura R.
  • Journal Title: Gynecol Oncol. 111(2) Pages: 312-319
• [Journal Article] Germ cell specific protein VASA is over-expressed in epithelial ovarian cancer and disrupts DNA damage-induced G2 checkpoint. (2008)
  • Author(s): Hashimoto H, Sudo T
  • Journal Title: Gynecologic Oncology 111(2) Pages: 312-319
  • Peer Reviewed
• [Journal Article] Estrogen receptor subtypes selectively mediate female mouse reproductive abnormalities induced by neonatal exposure to estrogenic chemicals (2008)
  • Author(s): Nakamura, T., Iguchi, T
  • Journal Title: Toxicology 253 Pages: 117-124
  • Peer Reviewed
• [Presentation] HPVゲノムのメチル化状態による子宮頸部上皮内病変の進展予測 (2010)
  • Author(s): 須藤保
  • Organizer: 第62回日本産婦人科学会学術講演会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2010-04-23
• [Presentation] HPVゲノムのメチル化状態による子宮頸部上皮内病変の進展予測 (2010)
  • Organizer: 第61回日本産婦人科学会
• [Presentation] 上皮性卵巣癌におけるPak1活性化とその特異的阻害剤Pak18の臨床応用の可能性 (2009)
  • Author(s): 橋本尚, 須藤保
  • Organizer: 日本産婦人科学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2009-04-05
• [Presentation] 上皮性卵巣癌におけるPak1活性化と特異的阻害剤Pak18の臨床応用の可能性 (2009)
  • Organizer: 第61回日本産婦人科学会
• [Presentation] 上皮性卵巣癌におけるPak1活性化と特異的阻害剤Pak18の臨床応用の可能性 (2009)
  • Organizer: 第68回日本癌学会
• [Presentation] HPVゲノムのメチル化状態による子宮頸部上皮内病変の進展予測 (2009)
  • Organizer: 第68回日本癌学会
• [Presentation] 上皮性卵巣癌におけるPak1活性化と特異的阻害剤Pak18の臨床応用の可能性 (2009)
  • Organizer: 第47回日本癌治療学会
• [Book] Modern genetics of reproductive biology. (2010)
  • Author(s): Iguchi, T., Miyagawa, S., Sudo, T., Woodruff, T., Janssen, S.J., Guillette, L.J.Jr., Giudice, L.C.
  • Publisher: Environmental Impacts on Reproductive Health and Fertility Cambridge University Press
• [Book] Modern genetics of reproductive biology. In : Environmental Impacts on Reproductive Health and Fertility (2010)
  • Author(s): Iguchi, T., Miyagawa, S., Sudo, T., Woodruff, T., Janssen, S.J., Guillette, L.J.Jr., Giudice, L.C.
  • Publisher: Cambridge University Press
• [Book] Environmental Impacts on Reproductive Health and Fertility (2009)
  • Author(s): Taisen Iguchi, Shinichi Miyagawa, Tamotsu Sudo
  • Total Pages: 262
  • Publisher: Cambridge University Press
• [Remarks] ホームページ等