ヒト骨肉腫はエストロゲンを産生するか?

• Project/Area Number: 20659053
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Human pathology
• Research Institution: Tohoku University
• Principal Investigator: 笹野 公伸 Tohoku University, 大学院・医学系研究科, 教授 (50187142)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,100,000 (Direct Cost: ¥3,100,000); Fiscal Year 2009: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2008: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: 骨 / 骨肉腫 / 骨芽細胞 / aryl hydrocarbon receptor / エストロゲン / アロマターゼ / 肉腫 / 性ステロイド / プロゲステロン / アンドロゲン / ホルモン

Research Abstract

前回我々はestrogenic compounds(bisphenol A)のSteroid and xenobiotic receptorを介した作用を報告した。今回、SXRと同様にcytochrome P450の制御に関わるaryl hydrocarbon receptor(AhR)に注目し、正常骨組織から骨肉腫までの作用について検討を行った。免疫組織化学の結果、正常骨組織ではAhRは骨芽細胞に発現することが明らかとなった。また、骨芽細胞の培養細胞(hFOB)を用いたマイクロアレイ解析(human 1A : Agilent Technologies)ではestrogen receptor beta(ERbeta)、エストロゲン合成酵素であるアロマターゼ、エストロゲン代謝酵素であるCYP1Bの制御に関わることが明らかとなった。骨肉腫培養細胞株MG-63およびhFOBを用いた定最的PCRにおいても、AhRリガンドである3-methylcholanthreneの添加によってERbeta、アロマターゼ、CYP1Bの発現増加を認めた。以上のことから、AhRは骨芽細胞においてエストロゲン作用の調節に関与することが示唆された。一方、ヒト骨肉腫組織を用いた免疫組織化学では、骨肉腫組織にBRbetaが発現することを確認したが、アロマターゼの発現は認められなかった。このことから正常骨細胞と癌細胞においては、AhRの性質、特に応答遺伝子の発現パターンが大きく異なり、エストロゲンシグナルを介した骨肉腫の病体と関連することが示唆された。

Research Products

• [Journal Article] Highly concordant coexpression of aromatase and estrogen receptor beta in non-small cell lung cancer. (2010)
  • Author(s): Abe K, Miki Y, Ono K, Mori M, Kakinuma H, Kou Y, Kudo N, Koguchi M, Niikawa H, Suzuki S, Evans DB, Sugawara S, Suzuki T, Sasano H.
  • Journal Title: Hum Pathol. 41 Pages: 190-198
  • Peer Reviewed
• [Journal Article] Aromatase and in situ estrogen production in DCIS (ductal carcinoma in situ) of human breast. (2010)
  • Author(s): Sasano H, Miki Y, Shibuya R, Suzuki T.
  • Journal Title: J Steroid Biochem Mol Biol. 118 Pages: 242-245
  • Peer Reviewed
• [Journal Article] Breast cancer aromatase expression evaluated by the novel antibody 677 : Correlations to intra-tumor estrogen levels and hormone receptor status. (2010)
  • Author(s): Geisler J, Suzuki T, Helle H, Miki Y, Nagasaki S, Duong NK, Ekse D, Aas T, Evans DB, Lonning PE, Sasano H.
  • Journal Title: J Steroid Biochem Mol Biol. 118 Pages: 237-241
  • Peer Reviewed
• [Journal Article] Epitope characterization of an aromatase monoclonal antibody suitable for the assessment of intratumoral aromatase activity. (2009)
  • Author(s): Hong Y, Li H, Ye J, Miki Y, Yuan YC, Sasano H, Evans DB, Chen S.
  • Journal Title: PLoS One 4
  • Peer Reviewed
• [Journal Article] In situ estrogen production and its regulation in human breast carcinoma : from endocrinology to intracrinology. (2009)
  • Author(s): Sasano H, Miki Y, Nagasaki S, Suzuki T.
  • Journal Title: Pathol Int 59 Pages: 777-789
  • NAID: 10027382046
  • Peer Reviewed
• [Journal Article] Steroid hormones are produced at the sites of action. (2009)
  • Author(s): Sasano H.
  • Journal Title: Endocr J 56 Pages: 825-826
  • NAID: 10026915077
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of 17beta-hydroxysteroid dehydrogenase type 12 by SREBP-1. (2009)
  • Author(s): Nagasaki S, Miki Y, Akahira J, Suzuki T, Sasano H.
  • Journal Title: Mol Cell Endocrinol 307 Pages: 163-168
  • Peer Reviewed
• [Journal Article] The mediator complex subunit 1 enhances transcription of genes needed for adrenal androgen production. (2009)
  • Author(s): Nakamura Y, Xing Y, Sasano H, Rainey WE.
  • Journal Title: Endocrinology 150 Pages: 4145-4153
  • Peer Reviewed
• [Journal Article] 17beta-hydroxysteroid dehydrogenase type 11 (Pan1b) expression in human prostate cancer. (2009)
  • Author(s): Nakamura Y, Suzuki T, Arai Y, Sasano H.
  • Journal Title: Neoplasma 56 Pages: 317-320
  • Peer Reviewed
• [Journal Article] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro : estrogen receptor dependent or independent pathways of raloxifene. (2009)
  • Author(s): Miki Y, Suzuki T, Nagasaki S, Hata S, Akahira J, Sasano H.
  • Journal Title: J Steroid Biochem Mol Biol 113 Pages: 281-289
  • Peer Reviewed
• [Journal Article] 17beta-hydroxysteroid dehydrogenases in human breast cancer. (2009)
  • Author(s): Nagasaki S, Miki Y, Akahira J, Suzuki T, Sasano H.
  • Journal Title: Ann N Y Acad Sci 1155 Pages: 25-32
  • Peer Reviewed
• [Journal Article] 17Beta-hydroxysteroid dehydrogenase type 12 in human breast carcinoma : a prognostic factor via potential regulation of fatty acid synthesis (2009)
  • Author(s): Nagasaki S, Suzuki T, Miki Y, Akahira J, Kitada K, Ishida T, Handa H, Ohuchi N, Sasano H.
  • Journal Title: Cancer Res 69 Pages: 1392-1399
  • Peer Reviewed
• [Journal Article] Aromatase expression and outcomes in the P024 neoadjuvant endocrine therapy trial (2009)
  • Author(s): Ellis MJ, Miller WR, Tao Y, Evans DB, Chaudri Ross HA, Miki Y, Suzuki T, Sasano H.
  • Journal Title: Breast Cancer Res Treat (in press)
  • Peer Reviewed
• [Journal Article] Chicken ovalbumin upstream promoter transcription factor II in human breast carcinoma : Possible regulator of lymphangiogenesisvia vascular endothelial growth factor-C expression (2009)
  • Author(s): Nagasaki S, Suzuki T, Miki Y, Akahira JI, Shibata H, Ishida T, Ohuchi N, Sasano H.
  • Journal Title: Cancer Sci (in press)
  • Peer Reviewed
• [Journal Article] DAX-1A(NROB1A)Expression Levels are Extremely Low Compared to DAX-1(NROBI)in Human Steroidogenic Tissues (2009)
  • Author(s): Nakamura Y, Vargas Morris C, Sasano H, Rainey WE.
  • Journal Title: Horm Metab Res 41 Pages: 30-34
  • Peer Reviewed
• [Journal Article] Nuclear Receptor DAX1 in Human Prostate Cancer : A Novel Independent Biological Modulator (2009)
  • Author(s): Nakamura Y, Suzuki T, Arai Y, Sasano H.
  • Journal Title: Endocr J 56 Pages: 39-44
  • NAID: 10025610118
  • Peer Reviewed
• [Journal Article] Steroid Sulfatase and Estrogen Sulfotransferase in Colon Carci coma : Regulators of Intratumoral Estrogen Concentrations and Potent Prognostic Factors (2009)
  • Author(s): Sato R, Suzuki T, Katayose Y, Miura K, Shiiba K, Tateno H, Miki Y, Akahira J, Kamogawa Y, Nagasaki S, Yamamoto K, Ii T, Egawa S, Evans DB, Unno M, Sasano H.
  • Journal Title: Cancer Res 69 Pages: 914-922
  • Peer Reviewed
• [Journal Article] 17beta-hydroxysteroid dehydrogenases in human breast cancer (2009)
  • Author(s): Nagasaki S, Miki Y, Akahira T. Suzuki T. Sasano H.
  • Journal Title: Ann N Y Acad Sci 1155 Pages: 25-32
  • Peer Reviewed
• [Journal Article] New developments in intracrinology of human breast cancer : estrogen sulfatase and sulfotransferase (2009)
  • Author(s): Sasano H, Nagasaki S, Miki Y, Suzuki T.
  • Journal Title: Ann N Y Acad Sci 1155 Pages: 76-79
  • Peer Reviewed
• [Journal Article] Loss of estrogen receptor beta isoform expression and its corr elation with aberrant DNA methylation of the 5'-untranslated region in human epithelial ovarian carcinoma (2008)
  • Author(s): Suzuki F, Akahira J, Miura I, Suzuki T, Ito K, Hayashi S, Sasano H, Yaegashi N.
  • Journal Title: Cancer Sci 99 Pages: 2365-2372
  • Peer Reviewed
• [Presentation] Increased estrogen sulfatase (STS) and 17ss-hydroxysteroid dehydrogenase type1 (17ss-HSD1) after neoadjuvant aromatase inhibitor therapy in breast cancer patients (2010)
  • Author(s): N Chanplakorn, P Chanplakorn, K Ono, Y Miki, S Saji, T Ueno, M Toi, 笹野公伸
  • Organizer: 6th Annual Conference of OOTR
  • Place of Presentation: ウェスティン都ホテル京都(京都府)
  • Year and Date: 2010-02-26
• [Presentation] 10%ホルマリン固定パラフィン包埋標本から抽出したTotalRNAおよびmicroRNAの質的検討 (2009)
  • Author(s): 三浦伊久美、三木康宏、赤平純一、鈴木貴、笹野公伸
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2009-05-02
• [Presentation] Controversies in Endocrine Treatment : Effective utilization of steroidal and non-steroidal aromatase inhibitors-Now and in the Future. (2009)
  • Author(s): 笹野公伸
  • Organizer: Taiwan Aromatase Conference
  • Place of Presentation: NTUH International Convention Center(Taiwan)
  • Year and Date: 2009-04-19
• [Presentation] Gene Profiling and histopathological analysis in early breast carcinoma-advantages and limitations (2009)
  • Author(s): 笹野公伸
  • Organizer: Kyoto Breast Cancer Consensus Conference 2009
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2009-04-17
• [Presentation] Intratumoral estrogen production in human breast cancer-Its regulation and inhibition (2009)
  • Author(s): 笹野公伸
  • Organizer: The Endocrine Society of Australia 52nd Annual Scientific Meeting
  • Place of Presentation: Adelaide Convention Center(Australia)
• [Presentation] Intracrinology of Estorogen and Androgens in Human Breast Care inoma (2008)
  • Author(s): H Sasano, Y Miki, S Nagasaki, T Suzuki
  • Organizer: 13^<th> International Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: Quebec Hilton (Canada)
  • Year and Date: 2008-09-29
• [Presentation] Comparative Effects of Raloxifene,Tamoxifen and Estradiol on Human Osteoblast In Vitro (2008)
  • Author(s): Y Miki, S Nagasaki, S Hata, J-I Akahira, T Suzuki, H Sasano
  • Organizer: The Endocrine Society's 90th Annual Meeting
  • Place of Presentation: San Francisco Convention Center(USA)
• [Presentation] Gene Profiling of the Reticularis and Fasciculata Zones of Hum an Adult Adrenals (2008)
  • Author(s): Y Nakamura, PJ Hornsby, PR Casson, R Morimoto, F Satoh H Sasano, WE Rainey
  • Organizer: The Endocrine Society's 90th Annual Meeting
  • Place of Presentation: San Francisco Convention Center(USA)
• [Presentation] Does DAX1A(NROBIA)Play a Role in Adrenal Function? (2008)
  • Author(s): Y Nakamura, CV Morris, H Sasano, WE Rainey
  • Organizer: The Endocrine Society's 90th Annual Meeting
  • Place of Presentation: San Francisco Convention Center(USA)
• [Presentation] The Expression of steroid sulfatase and Estrogen Sulfotransferase In Human Epithelial Ovarian Cancer (2008)
  • Author(s): J-I Akahira, T Suzuki, F Suzuki, I Miura, Y Miki, K Ito, N Yaegashi, H Sasano
  • Organizer: The Endocrine Society's 90th Annual Meeting
  • Place of Presentation: San Francisco Convention Center(USA)
• [Presentation] Intracrinology of sex-steroids in ductal carcinoma In situ(DCIS)of the breast : comparison to invasive Ductal carcinoma(IDC)and non-neoplastic breas (2008)
  • Author(s): H Sasano, Y Miki, R Shibuya, I Suzuki
  • Organizer: 18th International symposium of the journal of steroid Biochemistry and molecular biology
  • Place of Presentation: Conference Center -Seefeld (Austria)
• [Presentation] Proliferative effect of estrogen on human lung cancer in vitro -Aromatase as a possible target for human lung cancer therapy- (2008)
  • Author(s): Y Miki, H Niikawa, K Abe, S Suzuki, S Hata, J Akahira, T Suzuki, H Sasano
  • Organizer: 13^<th> International Congress on Hormonal Ster oids and Hormones & Cancer
  • Place of Presentation: Quebec Hilton (Canada)
• [Presentation] Immunolocalization of COUP-TF in human breast carcinoma : a possible prognostic factor (2008)
  • Author(s): S Nagasaki, T Suzuki, Y Miki,.T Akahira. H Sasano
  • Organizer: 13^<th> International Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: Quebec Hilton (Canada)
• [Presentation] Aromatase and in situ estrogen production in DCIS(ductal carcinoma in situ) of human breast (2008)
  • Author(s): H Sasano, Y Miki, R Shibuya, T Suzuki
  • Organizer: Ninth International Aromatase Conference
  • Place of Presentation: Shanghai(China)