Targeting the molecules useful for the diagnosis and treatment of endometrial cancers

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 17390448
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kanazawa University
• Principal Investigator: INOUE Masaki Kanazawa University, Graduate School Of Medical Science, Prof (10127186)
• Co-Investigator(Kenkyū-buntansha): KYO Satoru Kanazawa University, Graduate School of Medical Science, Associate (50272969) ; TANAKA Masaaki Kanazawa University, OBGYN, Associate (70283140)
• Project Period (FY): 2005 – 2007
• Keywords: Molecular carcinogenesis / Molecular targets / Endometrial cancer / Therapeutic agent / Prognostic Markers

Research Abstract

Endometrial cancer is the second most common gynecological malignancy and its incidence has increased dramatically over the last decade in Japan. Although the surgical and chemotherapeutic treatments for endometrial cancers are well-established, the need for molecular-target therapy has increased, especially for recurrent and/or radio- or chemo-resistant diseases. Thus there is a need for a better understanding of the molecular pathway of endometrial carcinogens.
The most frequent genetic abnormalities are mutations in PTEN and ERAS. A PTEN mutation and ERAS mutation activates the PI3K pathway and ERK - MAP pathway, respectively. In the present study using the clinical samples, there is no significant association between KRAS or BRAF and p-ERK1/2 expression. Patients with low expression have a favorable prognosis. Thus, the activation of ERK1/2 occurs in a ERAS and BRAF I dependent manner in endometrial cancer. A High level of p-AKT expression was observed in approximately 60% of endometrial cancers. It occurs independently of both PTEN mutations and PIK3CA mutations. Furthermore, p-AKT expression did not correlated with expression of potential downstream targets such as p-mTOR and/or p TORO 1/3a. The high-expression of p-AKT was strongly associated with ERK. The present study revealed the presence of complex signaling pathways other than the conventional carcinogenic pathway. The molecular targeting for the diagnosis and treatment of endometrial cancers is a long way for the success.

Research Products

• [Journal Article] Activation of ERK1/2 occurs independently of KRas orBraf status in endometrial cancer and is associated with favorable prognosis. (2007)
  • Author(s): Mizumoto Y, Kyo S, Mori N, Sakaguchi J, Ohno S, Maida Y, Hashimoto M, Takakura M, Inoue M.
  • Journal Title: Cancer Science 98 Pages: 6652-6658
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Analysis of outcome of stage I-III endometrial cancer treated with systematic operation omitting paraaortic lymphadenectomy (2007)
  • Author(s): Kyo, S., Hashimoto, M., Maida, Y., Mizumoto, Y., Nakamura, M., Takakura, M., Inoue, M
  • Journal Title: Eur J Gynecol Oncol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activation of ERK1/2 occurs independently of KRas orBraf status in endometrial cancer and is associated with favorable prognosis (2007)
  • Author(s): Mizumoto, Y., Kyo, S., Mori, N., Sakaguchi, J., Ohno, S., Maida, Y., Hashimoto, M., Takakura, M., Inoue, M
  • Journal Title: Cancer Science 98 Pages: 6652-6658
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements. (2006)
  • Author(s): Mizumoto Y, Kyo S, Ohno S, Hashimoto M, Nakamura M, Maida Y, Sakaguchi J, Takakura M, Inoue M, Kiyono T
  • Journal Title: Oncogene 2006 25 Pages: 5673-5682
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] High Twist expression in involved in infiltrative endometrial cancer and affects patient survival. (2006)
  • Author(s): Kyo S, Sakaguchi J, Ohno S, Mizumoto Y, Maida Y, Hashimoto M. Nakamura M, Takakura M, Nakajima M, Masutomi K, Inoue M.
  • Journal Title: Human Pathol 37 Pages: 431-438
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The evaluation of human papilloma Virus DNA testing in primary screening for cervical lesions in a large Japanese population. (2006)
  • Author(s): Inoue M, Sakaguchi J, Sasagawa T, Tango S.
  • Journal Title: Int J Gynecol Cancer 16 Pages: 1007-1013
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of Tn and Sialy-Tn antigens in endometrial cancer. Its relationship with tumor-produced cyclooxygenase-2, tumor-infiltrated lymphocytes and patients prognosis. (2006)
  • Author(s): Ohono S, Ohno Y, Nakada H, Suzuki N, Soma G, Inoue M.
  • Journal Title: Anticancer Research 26 Pages: 4047-4054
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Distinct telomere length regulation in premalignant cervical and endometrial lesions: implicationsnfor the roles of telomeres in uterine carcinogenesis. (2006)
  • Author(s): Maida Y, Kyo S, Forsyth NR, Takakura M, Sakaguchi J, Mizumoto Y, Hashimoto Y, Nakamura M, Nakao S, Inoue M.
  • Journal Title: J Pathol 210 Pages: 214-223
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Novel function single nucleotide polyphisms in the latent TGF-binding protein1-L(LTBP-1L)Promoter. Effect on LTBP-1L expression level and possible prognostic significance in ovarian cancer. (2006)
  • Author(s): Higashi T, Kyo S, Inoue M, Tanii H, Saijoh K.
  • Journal Title: J. Mol Diag 8 Pages: 342-350
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements (2006)
  • Author(s): Mizumoto, Y., Kyo, S., Ohno, S., Hashimoto, M., Nakamura, M., Maida, Y., Sakaguchi, J., Takakura, M., Inoue, M., Kiyono, T
  • Journal Title: Oncogene
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High Twist expression in involved in infiltrative endometrial, cancer and affects patient survival (2006)
  • Author(s): Kyo, S., Sakaguchi, J., Ohno, S., Mizumoto, Y., Maida, Y., Hashimoto, M., Nakamura, M., Takakura, M., Nakajima, M., Masutomi, K., Inoue, M
  • Journal Title: Human Pathol 37 Pages: 431-438
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The evaluation of human papillomaVirus DNA testing in primary screening for cervical lesions in a large Japanese population (2006)
  • Author(s): Inoue, M., Sakaguchi, J., Sasagawa, T., Tango, S
  • Journal Title: Int J Gynecol Cancer 16 Pages: 1007-1013
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of Tn and Sialy-Tn antigens in endometrial cancer. Its relationship with tumor-produced cyclooxygenase-2, tumor-infiltrated lymphocytes and patients prognosis (2006)
  • Author(s): Ohono, S., Ohno, Y., Nakada, H., Suzuki, N., Soma, G., Inoue, M
  • Journal Title: Anticancer Research 26 Pages: 4047-4054
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct telomere length regulation in premalignant cervical and endometrial lesions : implicationsnfor the roles of telomeres in uterine carcinogenesis (2006)
  • Author(s): Maida, Y., Kyo, S., Forsyth, NR., Takakura, M., Sakaguchi, J., Mizumoto, Y., Hashimoto,Y., Nakamura, M., Nakao, S., Inoue, M
  • Journal Title: J Pathol 210 Pages: 214-223
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Novel function single nucleotide polyphisms in the latent TGF-binding proteinl-L(LTBP-1L) Promoter. Effect on LTBP-1L expression level and possible prognostic significance in ovarian cancer (2006)
  • Author(s): Higashi, T., Kyo, S., Inoue, M., Tanii, H., Saijoh, K
  • Journal Title: J. Mol Diag 8 Pages: 342-350
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of cyclooxygenase-2 in immunomodulation and prognosis of endometrial carcinoma. (2005)
  • Author(s): Ohno Y, Ohno S, Suzuki N, Kamei T, Inagawa H, Soma G, Inoue M.
  • Journal Title: Int J Cancer 114 Pages: 696-701
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1 (2005)
  • Author(s): Nakajima M, Fujiki Y, Kyo S, Nakamura M, Maida Y, Tanaka M, Inoue M.
  • Journal Title: J Clin Pharmacol 45 Pages: 674-682
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Efficient inhibition of human telomerase reverse transcriptase expression by RNA interference sensitizes cancer cells to ionizing radiation and chemotherapy. (2005)
  • Author(s): Nakamura M, Masutomi K, Kyo S, Hashimoto M, Maida Y, Kanaya T, Tanaka M, Hahn WC, Inoue M.
  • Journal Title: Human gene therapy 16 Pages: 859-868
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Analysis of telomerase single-strand overhang in human endometrial cancers. (2005)
  • Author(s): Hashimoto M, Kyo S, Masutomi K, Maida Y, Sakaguchi J, Mizumoto Y, Nakamura M, Hahn WC, Inoue M
  • Journal Title: FEBS letter 579 Pages: 2959-2964
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Association of mismatch repair deficiency with PTEN frameshift mutations in endometrial cancers and the precursors in a Japanese population (2005)
  • Author(s): Kanaya T, Kyo S, Sakaguchi J, Maida Y, Nakamura M, Takakura M, Hashimoto M, Mizumoto Y, Inoue M.
  • Journal Title: Am J Clin Pathol 124 Pages: 89-96
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Wright WE, Shay JW. The function of AP1 on transcription of telomerase reverse transcriptase gene(TERT)in human and mouse cell. (2005)
  • Author(s): Takakura M, Kyo S, Inoue M,
  • Journal Title: Mol Cell Biol 18 Pages: 8037-8043
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Aromatase expression in stromal cells of endometrioid endometrial cancer correlates with poor survival. (2005)
  • Author(s): Segawa T, Shozu M, Murakami K, Kasai T, Shinohara K, Nomura K, Ohno S, Inoue M.
  • Journal Title: Clin Cancer Res 11 Pages: 2188-2194
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] K. ADAMTS-1 is involved in normal follicular development, ovulatory process and organization of the medullary vascular network in the ovary. (2005)
  • Author(s): Shozu M, Minami N, Yokoyama H, Inoue M, Kurihara H, Matsushima K, Kuno
  • Journal Title: J Mol Endocrinol 35 Pages: 343-355
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of cyclooxygenase-2 in immunomodulation and prognosis of endometrial carcinoma (2005)
  • Author(s): Ohno, Y., Ohno, S., Suzuki, N., Kamei, T., Inagawa, H., Soma, Q., Inoue, M
  • Journal Title: Int J Cancer 114 Pages: 696-701
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDRI (2005)
  • Author(s): Nakajima, M., Fujiki, Y., Kyo, S., Nakamura, M., Maida, Y., Tanaka, M., Inoue, M
  • Journal Title: J Clin Pharmacol 45 Pages: 674-682
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efficient inhibition of human telomerase reverse transcriptase expression by RNA interference sensitizes cancer cells to ionizing radiation and chemotherapy (2005)
  • Author(s): Nakamura, M., Masutomi, K., Kyo, S., Hashimoto, M., Maida,Y., Kanaya, T., Tanaka, M., Hahn, WC., Inoue, M
  • Journal Title: Human gene therapy 16 Pages: 859-868
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of telomerase single-strand overhang in human endometrial cancers (2005)
  • Author(s): Hashimoto, M., Kyo, S., Masutomi, K., Maida, Sakaguchi, J., Mizumoto, Y., Nakamura, M., Hahn, WC., Inoue, M
  • Journal Title: FEBS letter 579 Pages: 2959-2964
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of mismatch repair deficiency with PTEN frameshift mutations in endometrial cancers and the precursors in a Japanese population (2005)
  • Author(s): Kanaya, T., Kyo, S., Sakaguchi, J., Maida, Y., Nakamura, M., Takakura, M., Hashimoto, M., Mizumoto, Y., Inoue, M
  • Journal Title: Am J Clin Pathol 124 Pages: 89-96
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The function of API on transcription of telomerase reverse transcriptase gene (TERT) in human and mouse cell (2005)
  • Author(s): Takakura, M., Kyo, S., Inoue, M., Wright, WE., Shay, JW
  • Journal Title: Mol Cell Biol 18 Pages: 8037-8043
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aromatase expression in stromal cells of endometrioid endometrial cancer correlates with poor survival (2005)
  • Author(s): Segawa, T., Shozu, M., Murakami, K., Kasai, T., Shinohara, K., Nomura, K., Ohno, S., Inoue, M
  • Journal Title: Clin Cancer Res 11 Pages: 2188-2194
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ADAMTS-1 is involved in normal follicular development, ovulatory process and organization of the medullary vascular network in the ovary (2005)
  • Author(s): Shoat, M., Minami, N., Yokoyama, H., Inoue, M., Kurihara, H., Matsushima, K., Kuno, K
  • Journal Title: J Mol Endocrnol 35 Pages: 343-355
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of outcome of stage I-III endometrial cancer treated with systematic operation omitting paraaortic lymphadenectomy.
  • Author(s): Kyo S, Hashimoto M, Maida Y, Mizumoto Y, Nakamura M, Takakura M, Inoue M.
  • Journal Title: Eur J Gynecol Oncol 2007 (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Establishment of long-term culture model to study endometrial biology and carcinogenesis.
  • Author(s): Kyo S, Mizumoto Y, Kiyono T, Maida Y, Hashimoto M, Sakaguchi J, Takakura M, Inoue M.
  • Journal Title: Review Article. Reprod Oncol 2007 (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Establishment of long-term culture model to study endometrial biology and carcinogenesis
  • Author(s): Kyo, S., Mizumoto, Y., Kiyono, T., Maida, Y., Hashimoto, M., Sakaguchi, J., Takakura, M., Inoue, M
  • Journal Title: Review Article.Reprod Oncol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Cervical Cancer Screening with Combination of Pap and HPV DNA tests (2005)
  • Author(s): Inoue M
  • Organizer: AOGIN
  • Place of Presentation: Malaysia
  • Year and Date: 20050721-23
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 10代からのがん予防 (2007)
  • Author(s): 井上正樹
  • Total Pages: 246
  • Publisher: NHK出版
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 症例から学ぶ 婦人科腫瘍学入門 (2005)
  • Author(s): 井上正樹
  • Total Pages: 302
  • Publisher: 永井書店
  • Description: 「研究成果報告書概要(和文)」より