Effects of androgen receptor on aromatase expression

雄激素受体对芳香酶表达的影响

• 批准号: 22591422
• 负责人: HORIGUCHI Jun
• 金额: $ 2.83万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22591422/
• 关键词: アロマターゼ; アンドロゲン受容体; 乳癌; グルココルチコイド受容体; エストロゲン

Estrogen is a key regulator of the proliferation and differentiation of breast cancer cells. In addition to the estrogen supply from the ovary, estrogen is produced locally from androgen by aromatase. However, the regulation of aromatase gene expression in breast cancer has not yet been fully clarified.Retinoic acid receptor-related orphan receptor (ROR) alpha plays an important role in the differentiation of many organs by regulating the transcription of target genes. Because aromatase and RORalpha are expressed in breast cancer, the effect of RORalpha on aromatase gene expression was studied. RORalpha significantly augmented the expression of aromatase mRNA, particularly those containing exon I.4, in MCF7 cells, and aromatase activities in T47D and MCF7 cells. RORalpha also stimulated the proliferation of these cells. Transient transfection-based reporter gene assays using the promoter at exon I.4 showed that RORalpha augmented the transcription. A series of truncated mutation studies revealed that RORalpha activated the transcription through -147 to +14 bp of the promoter I.4. Furthermore, RORalpha bound to the fragment containing -119 to -107 bp of the promoter in vitro, indicating that this region may contain a novel ROR response element. Chromatin immunoprecipitation assay showed that RORalpha bound to the region containing this site of the promoter I.4 in MCF7 cells.Moreover, we examined clinical samples and found a correlation between RORalpha and aromatase expression. These results suggest that RORalpha directly activates the aromatase expression to accelerate the local production of estrogen, which results in the proliferation of breast cancer cells.

雌激素是乳腺癌细胞增殖和分化的关键调节因子。除了来自卵巢的雌激素供应外，雌激素还通过芳香化酶由雄激素局部产生。但芳香化酶基因在乳腺癌中的表达调控尚未完全阐明，视黄酸受体相关孤儿受体（ROR）α通过调控靶基因的转录，在许多器官的分化中发挥重要作用。因为芳香酶和ROR α在乳腺癌中表达，所以研究了ROR α对芳香酶基因表达的影响。ROR α显著增强了MCF 7细胞芳香化酶mRNA的表达，特别是那些含有外显子I.4的mRNA，以及T47 D和MCF 7细胞芳香化酶的活性。ROR α也刺激这些细胞的增殖。使用外显子I.4启动子的基于瞬时转染的报告基因测定显示ROR α增强了转录。一系列截短突变研究表明ROR α通过启动子I.4的-147至+14 bp激活转录。此外，ROR α在体外与含有启动子的-119至-107 bp的片段结合，表明该区域可能含有新的ROR反应元件。染色质免疫沉淀实验显示ROR α在MCF 7细胞中结合到包含启动子I.4的该位点的区域。此外，我们检查了临床样本，发现ROR α与芳香化酶表达之间存在相关性。这些结果表明，ROR α直接激活芳香化酶的表达，以加速雌激素的局部产生，从而导致乳腺癌细胞的增殖。

项目成果

Pathological Complete Response and Prognosis in Patients Receiving Neoadjuvant Paclifaxel and Trastuzumab with and without Anthracyclines for Stage II and III, HER2-positive Operable Breast Cancer : A Single-institute Experience

接受新辅助紫杉醇和曲妥珠单抗联合或不联合蒽环类药物治疗 II 期和 III 期 HER2 阳性可手术乳腺癌患者的病理完全缓解和预后：单机构经验

• 发表时间: 2011
• 期刊: Anticancer Res
• 影响因子: 2
• 作者: Nishimura N;Nakano K;Ueda K;Kodaira M;Yamada S;Mishima Y;Yokoyama M;Terui Y;Takahashi S;Hatake K;Ishikawa Y;Horiguchi J
• 通讯作者: Horiguchi J

教育講演「再発乳がんの治療と今後の展望～化学療法を中心に～」

教育讲座“复发性乳腺癌的治疗与未来展望——聚焦化疗”

• 发表时间: 2011
• 作者: J. Horiguchi;D. Takata;N. Rokutanda;R. Nagaoka;A. Sato;H. Tokiniwa;K. Tozuka;S. Uchida;M. Kikuchi;T. Oyama;I. Takeyoshi;堀口 淳;Horiguchi Jun;Rokutanda Nana;Tokiniwa Hideaki;堀口淳
• 通讯作者: 堀口淳

乳癌のホルモン療法～新たなホルモン治療選択～

乳腺癌的激素治疗~新的激素治疗选择~

• 发表时间: 2011
• 作者: J. Horiguchi;D. Takata;N. Rokutanda;R. Nagaoka;A. Sato;H. Tokiniwa;K. Tozuka;S. Uchida;M. Kikuchi;T. Oyama;I. Takeyoshi;堀口 淳;Horiguchi Jun;Rokutanda Nana;Tokiniwa Hideaki;堀口淳;堀口淳
• 通讯作者: 堀口淳

St Gallen2011結果よりみた乳癌内分泌療法の動向

基于圣加仑 2011 年结果的乳腺癌内分泌治疗趋势

• 发表时间: 2011
• 作者: J. Horiguchi;D. Takata;N. Rokutanda;R. Nagaoka;A. Sato;H. Tokiniwa;K. Tozuka;S. Uchida;M. Kikuchi;T. Oyama;I. Takeyoshi;堀口 淳;Horiguchi Jun;Rokutanda Nana;Tokiniwa Hideaki;堀口淳;堀口淳;堀口淳
• 通讯作者: 堀口淳

基礎と臨床の最新研究動向802

最新基础和临床研究动态802

• 发表时间: 2012
• 作者: Liu D;Kadota K;Ueno M;Nakashima N;Yokomise H;Huang CL.;合田 文則;伊藤佐智夫;小田原広樹
• 通讯作者: 小田原広樹