2001 Fiscal Year Annual Research Report

ヒト乳癌、子宮内膜癌における腫瘍組織局所でのエストロゲン合成調節機構の解明

Research Project

Project/Area Number	11470047
Research Institution	Tohoku University
Principal Investigator	笹野公伸東北大学, 医学系研究科, 教授 (50187142)
Co-Investigator(Kenkyū-buntansha)	高橋和広東北大学, 大学院・医学系研究科, 助教授 (80241628) 森谷卓也東北大学, 医学部附属病院, 助教授 (00230160) 鈴木貴東北大学, 大学院・医学系研究科, 助手 (10261629) 原田信広藤田保健衛生大学, 医学部, 教授 (00189705) 佐藤信二東北大学, 大学院・医学系研究科, 講師 (10142960)
Keywords	乳癌 / エストロゲン / アンドロゲン / プロゲステロン / ステロイド代謝 / steroid sulfatase / estrone sulfotransferase / 5α-reductase
Research Abstract	我々はヒト乳癌における性ステロイドの局所制御因子を明らかにする目的で以下の検討を行った。最初に不活型ステロイドであるestrone sulfate(ES)をestrone(E1)に変換するsteroid sulfatase(STS),E1をESに代謝するestrone sulfotransferase(EST)を113例で検討した。次にtestosterone(T)をより強力なandrogen(A)活性を有する5α-dihydrotestosterone(DHT)に変換するとともに、progesterone(P)を5α-dihydroprogesteroneに代謝する作用を有している5α-reductase(RT)の発現を60例で検討した。STSは84例(74%)、ESTは50例(44%)において腫瘍細胞に陽性像を認め、正常乳管上皮細胞も陽性であった。STS陽性乳癌は腫瘍径が大きい傾向があり(P=0.0047)、有意に再発しやすい傾向がみられた(P=0.0315)。一方ESTは腫瘍径が小さく(P=0.0030)リンパ節転移が少ない傾向があり(P=0.0027)、有意に再発しにくくかつ予後良好であった(P=0.0069)。また多変量解析の結果、ESTはリンパ節転移(P=0.0087)とともに独立した予後因子であることが明らかとなった(P=0.0149)。以上の所見から、ヒト浸潤性乳管癌ではestrogen供給がSTSやESTによって制御されており、両者は乳癌の再発予後に関する重要な因子であることが示唆された。一方5α-RTtype1及びtype2は各々58%及び15%の症例において癌細胞質に陽性像を認め、同様の所見がRT-PCR(8例)でも確認された。5α-RT1の発現はandrogen receptor(AR)(p=0,0026)、progesterone receptor(PR)-A(p=0.039)、PR-B(p=0.042)、5α-RT2(p=0.030)、17β-HSD type5(p=0.0034)、3β-HSD(p=0.020)と相関する一方、腫瘍径(p=0.043)、histological grade(p=0.013)、Ki-67(P=0.020)と逆相関した。これらの検討からヒト浸潤性乳管癌では5α-RT1が多くの症例で癌細胞に発現し、局所におけるDHTの産生や作用に関与していると考えられた。更に5α-RT1陽性乳癌は、組織学的に分化度が高く増殖能が低い傾向が示された。

Research Products
(32 results)

All Other

All Publications (32 results)

[Publications] Brereton P et al.: "Pan1b (17betaHSD11)-enzymatic activity and distribution in the lung"Molecular and cellular Endocrinology. 171. 111-117 (2001)
[Publications] Takamura T et al.: "Adrenocorticotropin-independet unilateral adrenocortical hyperplasia with Cushing's syndrome : Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature"Pathology Intemational. 51. 118-122 (2001)
[Publications] Honma W et al.: "Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms"Drug metabolism and disposition. 29. 274-281 (2001)
[Publications] Suzuki T et al.: "Immunohistochemical distribution of 11beta-hydroxysteroid dehydrogenase in human eye"Molecular and cellular Endocrinology. 173. 121-125 (2001)
[Publications] Takahashi K et al.: "Expression of melanin-concentrating hormone receptor messenger ribonucleic acid in tumor tissues of pheochromocytoma, ganglioneuroblastoma, and neuroblastoma"Journal of Clinical Endocrinology & Metabolism. 86. 369-374 (2001)
[Publications] Muramatsu Y et al.: "Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries"Journal of Clinical Endocrinology & Metabolism. 86. 1362-1369 (2001)
[Publications] Suzuki T et al.: "Retinoid receptors in human breast carcinoma : possible modulators of in situ estrogen metabolism"Breast Cancer Research and Treatment. 65. 31-40 (2001)
[Publications] Suzuki S et al.: "Modulation of transalveolar fluid absorption by endogenous aldosterone in adult rats"Experimental Lung Research. 27. 143-155 (2001)
[Publications] Ariga N et al.: "Progesterone receptor a and b isoforms in the human breast and its disorders"Japanese Journal of Cancer Research. 92. 302-308 (2001)
[Publications] Meng L et al.: "Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma : mechanism of desmoplastic reaction"Cancer Research. 61. 2250-2255 (2001)
[Publications] Shimizu C et al.: "Interleukin-6 (IL-6) producing phaeochromocytoma : direct IL-6 suppression by non-steroidal anti-inflammatory drugs"Clinical Endocrinology (Oxf). 54. 405-410 (2001)
[Publications] Narasaka T et al.: "Temporal and spatial distribution of Corticosteroidogenic Enzymes Immunoreactivity in developing human adrenal"Molecular and cellular EndocrinologyMol. 28. 111-120 (2001)
[Publications] Suzuki T et al.: "5alpha-Rductases in human breast carcinoma : possible modulator of in situ androgenic actions"Journal of Clinical Endocrinology & Metabolism. 86. 2250-2257 (2001)
[Publications] Takeyama J et al.: "Expression and Cellular Localization of Estrogen Receptors alpha and beta in the Human Fetus"Journal of Clinical Endocrinology & Metabolism. 86. 2258-2262 (2001)
[Publications] Uzuki M et al.: "Urocortin in the synovial tissue of patients with rheumatoid arthritis"Clinical Science (Colch). 100. 577-589 (2001)
[Publications] Matuzaki S et al.: "Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis"Fertility and Sterility. 75. 1198-1205 (2001)
[Publications] Ito K et al.: "Retinoid receptors in the human endometrium and its disorders : a possible modulator of 17beta-hydroxysteroid dehydrogenase"Journal of Clinical Endocrinolgy and Metabolism. 86. 2721-2727 (2001)
[Publications] Makino S et al.: "A case of aldosterone-producing adrenocortical adenoma associated with preclinical Cushing's syndrome and hypersecretion of parathyroid hormone"Endocrine Journal. 48. 103-111 (2002)
[Publications] Cho YY et al.: "Abnormal uterus with polycysts, accumulation of uterine prostaglandins, and reduced fertility in mice heterozygous for acyl-coa synthetase 4 deficiency"Biochemical and Biophysical Research Communications :. 284. 993-997 (2001)
[Publications] Utsunomiya H et al.: "The analyses of 17beta-hydroxysteroid dehydrogenase isozymes in human endometrial hyperplasia and carcinoma"Joumal of Clinical Endocrinology and Metabolism. 86. 3436-3443 (2001)
[Publications] Moriya T et al.: "Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma"Pathology International. 51. 333-337 (2001)
[Publications] Ise T et al.: "A chimeric CYP11B1/CYP11B2 gene in glucocorticoid-insuppressible familial hyperaldosteronism"Clinical Endocrinology (Oxf). 55. 131-134 (2001)
[Publications] Midorikawa S et al.: "Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas : study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes"Endocrine Journal. 48. 167-174 (2001)
[Publications] Semba S et al.: "The cadherin-catenin superfamily in endocrine tumors"Endocrine Pathology. 12. 1-13 (2001)
[Publications] Inoue T et al.: "Spatial and topological distribution of progesterone receptor A and B isoforms during human development"Molecular and Cell Endocrinology. 182. 83-89 (2001)
[Publications] Sasano H et al.: "Estrogen receptor mRNA in situ hybridization using microprobe system"Methods Molecular Biology. 176. 317-325 (2001)
[Publications] Kumamoto H et al.: "Chromogenic in situ hybridization analysis of HER-2/neu status in breast carcinoma : application in screening of patients for trastuzumab (Herceptin) therapy"Pathology International. 51. 579-584 (2001)
[Publications] Totsune K et al.: "Role of urotensin II in patients on dialysis"The Lancet :. 358. 810-811 (2001)
[Publications] Nakamura Y et al.: "Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II"Endocrine J. 15. 57-61 (2001)
[Publications] Akahira Jl et al.: "Expression of 5alpha-reductases in human epithelial ovarian cancer : its correlation with androgen receptor status"Japanese Journal of Cancer Research. 92. 926-932 (2001)
[Publications] Sano T et al.: "17beta-Hydroxysteroid dehydrogenase type 2 expression and enzyme activity in the human gastrointestinal tract"Clinical Science (Lond). 101. 485-491 (2001)
[Publications] Suzuki T et al.: "EBAG9/RCAS1 in human breast carcinoma : a possible factor in endocrine-immune interactions"British Journal of Cancer. 85. 1731-1737 (2001)

2001 Fiscal Year Annual Research Report

ヒト乳癌、子宮内膜癌における腫瘍組織局所でのエストロゲン合成調節機構の解明

Principal Investigator

笹野 公伸 東北大学, 医学系研究科, 教授 (50187142)

Research Products

[Publications] Brereton P et al.: "Pan1b (17betaHSD11)-enzymatic activity and distribution in the lung"Molecular and cellular Endocrinology. 171. 111-117 (2001)

[Publications] Takamura T et al.: "Adrenocorticotropin-independet unilateral adrenocortical hyperplasia with Cushing's syndrome : Immunohistochemical studies of steroidogenic enzymes, ultrastructural examination and a review of the literature"Pathology Intemational. 51. 118-122 (2001)

[Publications] Honma W et al.: "Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms"Drug metabolism and disposition. 29. 274-281 (2001)

[Publications] Suzuki T et al.: "Immunohistochemical distribution of 11beta-hydroxysteroid dehydrogenase in human eye"Molecular and cellular Endocrinology. 173. 121-125 (2001)

[Publications] Takahashi K et al.: "Expression of melanin-concentrating hormone receptor messenger ribonucleic acid in tumor tissues of pheochromocytoma, ganglioneuroblastoma, and neuroblastoma"Journal of Clinical Endocrinology & Metabolism. 86. 369-374 (2001)

[Publications] Muramatsu Y et al.: "Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries"Journal of Clinical Endocrinology & Metabolism. 86. 1362-1369 (2001)

[Publications] Suzuki T et al.: "Retinoid receptors in human breast carcinoma : possible modulators of in situ estrogen metabolism"Breast Cancer Research and Treatment. 65. 31-40 (2001)

[Publications] Suzuki S et al.: "Modulation of transalveolar fluid absorption by endogenous aldosterone in adult rats"Experimental Lung Research. 27. 143-155 (2001)

[Publications] Ariga N et al.: "Progesterone receptor a and b isoforms in the human breast and its disorders"Japanese Journal of Cancer Research. 92. 302-308 (2001)

[Publications] Shimizu C et al.: "Interleukin-6 (IL-6) producing phaeochromocytoma : direct IL-6 suppression by non-steroidal anti-inflammatory drugs"Clinical Endocrinology (Oxf). 54. 405-410 (2001)

[Publications] Narasaka T et al.: "Temporal and spatial distribution of Corticosteroidogenic Enzymes Immunoreactivity in developing human adrenal"Molecular and cellular EndocrinologyMol. 28. 111-120 (2001)

[Publications] Suzuki T et al.: "5alpha-Rductases in human breast carcinoma : possible modulator of in situ androgenic actions"Journal of Clinical Endocrinology & Metabolism. 86. 2250-2257 (2001)

[Publications] Takeyama J et al.: "Expression and Cellular Localization of Estrogen Receptors alpha and beta in the Human Fetus"Journal of Clinical Endocrinology & Metabolism. 86. 2258-2262 (2001)

[Publications] Uzuki M et al.: "Urocortin in the synovial tissue of patients with rheumatoid arthritis"Clinical Science (Colch). 100. 577-589 (2001)

[Publications] Matuzaki S et al.: "Expression of estrogen receptor alpha and beta in peritoneal and ovarian endometriosis"Fertility and Sterility. 75. 1198-1205 (2001)

[Publications] Ito K et al.: "Retinoid receptors in the human endometrium and its disorders : a possible modulator of 17beta-hydroxysteroid dehydrogenase"Journal of Clinical Endocrinolgy and Metabolism. 86. 2721-2727 (2001)

[Publications] Makino S et al.: "A case of aldosterone-producing adrenocortical adenoma associated with preclinical Cushing's syndrome and hypersecretion of parathyroid hormone"Endocrine Journal. 48. 103-111 (2002)

[Publications] Cho YY et al.: "Abnormal uterus with polycysts, accumulation of uterine prostaglandins, and reduced fertility in mice heterozygous for acyl-coa synthetase 4 deficiency"Biochemical and Biophysical Research Communications :. 284. 993-997 (2001)

[Publications] Utsunomiya H et al.: "The analyses of 17beta-hydroxysteroid dehydrogenase isozymes in human endometrial hyperplasia and carcinoma"Joumal of Clinical Endocrinology and Metabolism. 86. 3436-3443 (2001)

[Publications] Moriya T et al.: "Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma"Pathology International. 51. 333-337 (2001)

[Publications] Ise T et al.: "A chimeric CYP11B1/CYP11B2 gene in glucocorticoid-insuppressible familial hyperaldosteronism"Clinical Endocrinology (Oxf). 55. 131-134 (2001)

[Publications] Midorikawa S et al.: "Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas : study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes"Endocrine Journal. 48. 167-174 (2001)

[Publications] Semba S et al.: "The cadherin-catenin superfamily in endocrine tumors"Endocrine Pathology. 12. 1-13 (2001)

[Publications] Inoue T et al.: "Spatial and topological distribution of progesterone receptor A and B isoforms during human development"Molecular and Cell Endocrinology. 182. 83-89 (2001)

[Publications] Sasano H et al.: "Estrogen receptor mRNA in situ hybridization using microprobe system"Methods Molecular Biology. 176. 317-325 (2001)

[Publications] Kumamoto H et al.: "Chromogenic in situ hybridization analysis of HER-2/neu status in breast carcinoma : application in screening of patients for trastuzumab (Herceptin) therapy"Pathology International. 51. 579-584 (2001)

[Publications] Totsune K et al.: "Role of urotensin II in patients on dialysis"The Lancet :. 358. 810-811 (2001)

[Publications] Nakamura Y et al.: "Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II"Endocrine J. 15. 57-61 (2001)

[Publications] Akahira Jl et al.: "Expression of 5alpha-reductases in human epithelial ovarian cancer : its correlation with androgen receptor status"Japanese Journal of Cancer Research. 92. 926-932 (2001)

[Publications] Sano T et al.: "17beta-Hydroxysteroid dehydrogenase type 2 expression and enzyme activity in the human gastrointestinal tract"Clinical Science (Lond). 101. 485-491 (2001)

[Publications] Suzuki T et al.: "EBAG9/RCAS1 in human breast carcinoma : a possible factor in endocrine-immune interactions"British Journal of Cancer. 85. 1731-1737 (2001)

笹野公伸東北大学, 医学系研究科, 教授 (50187142)