Intracellular redox regulation on hormone-dependent proliferation of breast cancer

细胞内氧化还原调节乳腺癌激素依赖性增殖

• 批准号: 10470242
• 负责人: INAMOTO Takashi
• 金额: $ 8.26万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470242/
• 关键词: breast cancer; estrogen-dependent proliferation; thioredoxin(TRX); estorogen receptor; cell cycle regulation; redox regulation; hormone therapy

In this study, we obtained following results :1)By subcloning a breast cancer cell line, MCF-7, we revealed the subclones which expressed low level of intracellular thioredoxin (TRX) grew faster than those with high lever of TRX expression.2)Immunothistochemical analysis of tumor tissues of breast cancer patients showed that. in high intracellular TRX expression group, the estrogen receptor (ER) activity significantly related to the expression of pS-2. However, no relationship between ER activity and pS-2 expression in low TRX group. Moreover, p53 positive rate also related to mitotic index of tumor tissues in former group.3)In wild type p53 positive breast cancer cell line, p53-dependent p21 transcription activity was enhanced by TRX gene transfection.4)Analysis using mutant of ER (cystein to alanine) revealed that not only DNA-binding site but also legend binding region had high sensitive part to redox regulating by TRX.5)Redox factor1 (Ref-1) which is transcription factor related to redox regulation was mainly expressed as reduced type in uterine leiomyoma cells, and expressed as oxidised type in uterine smooth muscle. On the other hand ,TRX was expressed as oxidised type in uterine leiomyoma, and was expressed as reduced type in uterine smooth muscle.These results suggest that redox regulation on ER is important for biological activity of breast cancer, and that hormone therapy relating ER must be considered by the molecular mechanism of ER regulation.

本研究获得以下结果：1）通过亚克隆乳腺癌细胞系MCF-7，发现细胞内硫氧还蛋白（TRX）低表达的亚克隆生长速度快于TRX高表达的亚克隆; 2）乳腺癌患者肿瘤组织的免疫组化分析表明，TRX低表达的亚克隆生长速度快于TRX高表达的亚克隆。TRX高表达组雌激素受体（ER）活性与pS-2表达显著相关。低TRX组ER活性与pS-2表达无相关性。3）在野生型p53阳性乳腺癌细胞系中，TRX基因转染增强了p53依赖的p21转录活性。4）使用ER突变体的分析（半胱氨酸到丙氨酸）表明，不仅DNA结合位点，而且Legend结合区对TRX的氧化还原调节具有高敏感性。Ref-1）是与氧化还原调节相关的转录因子，在子宫肌瘤细胞中主要以还原型表达，在子宫平滑肌中主要以氧化型表达。TRX在子宫平滑肌瘤中呈氧化型表达，在子宫平滑肌中呈还原型表达，提示ER的氧化还原调节对乳腺癌的生物学活性有重要意义，ER相关激素治疗必须从ER调节的分子机制来考虑。

项目成果

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