Loss of BTG2 expression in breast cancer progression

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591906
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Juntendo University
• Principal Investigator: TAKAHASHI Fumiyuki 順天堂大学, 医学部, 准教授 (70327823)
• Co-Investigator(Kenkyū-buntansha): NARA Takeshi 順天堂大学, 医学部, 准教授 (40276473)
• Project Period (FY): 2011 – 2013
• Keywords: 乳癌 / BTG2 / 転移 / 上皮間葉転換 / Lapatinib

Research Abstract

EMT plays an important role in the tumor invasion and metastases. In human breast cancer, decreased BTG2 expression correlates with metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 plays a critical role in disease progression. To analyze the role of BTG2 in breast cancer, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhanced the motility of cells in vitro and enhanced tumor growth and metastasis in vivo. The effects of BTG2 knockdown were mediated through activation of HER2 and HER3, leading to elevated AKT phosphorylation. Suppression of HER activation using the lapatinib abrogated the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression, and raise the possibility that targeted inhibition of this pathway may be relevant in treatment breast cancers.

Research Products

• [Journal Article] Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. (2014)
  • Author(s): Murakami A, Takahashi F, Nurwidya F, Kobayashi I, Minakata K, Hashimoto M, Nar a T, et al.
  • Journal Title: PLoS One Volume: 28;9(1) Pages: e86459
• [Journal Article] Genistein attenuates hypoxic pulmonary hypertension via NO and erythropoietin system (2014)
  • Author(s): Kuriyama S, Morio Y, Toba M, Nagaoka T, Takahashi F, Seyama K, Takahashi K.
  • Journal Title: Am J Physiol - Lung Cell Mol Physiol Volume: (in press)
• [Journal Article] Tocilizumab, anti-interleukin 6 receptor antibody, the new approach to cancer cachexia (2013)
  • Author(s): Ando K, Takahashi F, Motojima S, Nakashima K, Kaneko N, Hoshi K, Takahashi K.
  • Journal Title: J Clin Oncol Volume: 31(6) Pages: e69-72
• [Journal Article] Chronic intermittent hypoxia/reoxygenation facilitate amyloid-ß generation in mice (2013)
  • Author(s): Shiota S, Takekawa H, Matsumoto S, Takeda K, Nurwidya F, Yoshioka Y, Takahashi F, Hattori N, Tabira T, Motizuki H, Takahashi K.
  • Journal Title: J Alzheimers Dis. Volume: 37(2) Pages: 325-33
• [Journal Article] HomeoboxB9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses (2012)
  • Author(s): Chiba N, Cornalis V, Shiotani B, Takahashi F, Shimada T., Tajima K., et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 109(8) Pages: 2760-5
• [Journal Article] Hypoxia induces gefitinib resistance in non-small cell lung cancer with both mutant and wild-type epidermal growth factor receptors. (2012)
  • Author(s): Minakata K, Takahashi F, Nar a T, Hashimoto M, Tajima K, Murakami A, Nurwidya F, et al.
  • Journal Title: Cancer Science Volume: 103(11) Pages: 1946-54
• [Journal Article] Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer (2012)
  • Author(s): Nurwidya F, Takahashi F, Murakami A, Takahashi K.
  • Journal Title: Cancer Res Treat Volume: 44 Pages: 151-6
• [Journal Article] a Kampo formula, ameliorates cancer cachexia induced by colon 26 adenocarcinoma in mice. (2012)
  • Author(s): Yae S, Takahashi F, Yae T, Yamaguchi T, Tsukada R, Koike K, Minakata K, Murakami A, Nurwidya F, Kato M, Tamada M, Yoshitake M, Kobayashi H, Seyama K, Takahashi K Hochuekkito (TJ-41)
  • Journal Title: Evidence-Based Complementary and Alternative Medicine Volume: 2012 Pages: 976926
• [Journal Article] Lung cancer stem cells : Tumor biology and clinical implications (2012)
  • Author(s): Nurwidya F, Murakami A, Takahashi F, Takahashi K.
  • Journal Title: Asia Pac J Clin Oncol Volume: 8 Pages: 217-222
• [Journal Article] Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER (2011)
  • Author(s): Takahashi F, Chiba N, Tajima K, Hayashida T, Shimada T, Takahashi M, et al.
  • Journal Title: inhibitor lapatinib Oncogene Volume: 30(27) Pages: 3084-95
• [Journal Article] 8. HoxB9, a gene overexpessed in breast cancer, promotes tumorigenicity and lung metastasis. (2010)
  • Author(s): Hayashida T, Takahashi F, Chiba N., Brachtel E., Takahashi M., et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 107(3) Pages: 1100-5
• [Journal Article] A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations (2010)
  • Author(s): Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al.
  • Journal Title: Cell Volume: 141(1) Pages: 69-80
• [Journal Article] Osteopontin mediates multidrug resistance of human mesothelioma cells through regulation of CD44 (2010)
  • Author(s): Tajima K, Ohashi R, Sekido Y, Hida T, Nar a T, Hashimoto M, Iwakami S, Minakata K, Yae T, Takahashi F, Saya H, and Takahashi K.
  • Journal Title: binding to hyaluronate Oncogene Volume: 29(13) Pages: 1941-51
• [Presentation] BTG2発現低下による癌悪性化とEGFR-TKI治療感受性の検討 (2012)
  • Author(s): 高橋史行、高橋元美、田島健ら
  • Organizer: 第52回日本呼吸器学会学術講演会
  • Year and Date: 20120000
• [Presentation] BTG2発現低下による癌悪性化および上皮間葉転換(EMT)のメカニズムの検討 (2011)
  • Author(s): 高橋史行、高橋元美、田島健ら
  • Organizer: 日本呼吸器学会学術講演会
  • Year and Date: 20110000