【摘要】 背景与目的:作为一类人工合成雌激素药物,二乙基己烯雌酚(diethyl-stilbestrol,DES)被广泛应用于治疗雌激素不足所致的更年期综合征及骨质疏松症等,但其对乳腺上皮细胞作用的研究有待进一步探讨。本研究通过建立与人相似的Wistar大鼠乳腺癌发生的模型,并用DES进行干预,观察DES在Wistar大鼠乳腺癌发生过程中的作用。方法:利用不同剂量的DES干预二甲基苯蒽[7,12-dimethylben(a)anthracene,DMBA]诱导Wistar大鼠乳腺癌模型,研究其对乳腺上皮细胞的作用。实验分为6个组:对照组、DES1组、DMBA组、DES1+DMBA组、DES2+DMBA组和DES3+DMBA组,其中DES1、DES2和DES3中DES剂量分别为:0.1mg·kg-1·d-1、0.2mg·kg-1·d-1和0.4mg·kg-1·d-1喂养大鼠,观察44周处死大鼠,取乳腺组织作常规病理分析以及核仁组成区相关嗜银蛋白(silver-binding nucleolar organizer regions,AgNOR)计数、PCNA染色强度指数(proliferating cell nuclear antigen staining intensity index,PCNA SII)、Bcl-2和C-erbB-2蛋白表达测定。结果:DMBA组和DES1+DMBA组分别有13只和2只Wistar大鼠发生癌变;单纯DES1组大鼠乳腺上皮细胞AgNOR计数及PCNASII水平上升,Bcl-2及C-erbB-2的表达提高,但未导致癌变;与其他组相比,DES2+DMBA组大鼠乳腺上皮细胞的AgNOR计数和PCNASII水平下降,Bcl-2及C-erbB-2的表达降低(P<0.05);DES3+DMBA组上述指标与DES1+DMBA组差异无统计学意义(P>0.05)。结论:单纯小剂量DES可导致大鼠乳腺上皮细胞增生,但不导致乳腺组织癌变;在DMBA诱发大鼠乳腺上皮细胞癌变过程中,小剂量DES可以促使乳腺导管上皮细胞增生、乃至癌变;而中等剂量DES可以明显抑制大鼠乳腺上皮细胞增生,加大DES剂量,抑制作用不增强。更多还原

【Abstract】 BACKGROUND & OBJECTIVE: As a synthesized estrogenic drug, diethylstilbestrol (DES) is generally used to cure diseases like climacteric period syndrome and osteoporosis due to estrogen insufficient, but its effect on mammary gland epithelial cells is still unclear. This study was to observe the effect of DES on dimethylbenzanthracene (DMBA)-induced carcinogenesis of breast cancer in Wistar rats. METHODS: A total of 90 Wistar rats were equally divided into control, DES1, DMBA, DES1 plus DMBA, DES2 plus DMBA, and DES3 plus DMBA groups. The rats were perfused with DMBA at a dose of 100 mg/kg on Days 1 and 30, and DES at a dose of 0.1 mg·kg-1·d-1 (DES1), 0.2 mg·kg-1·d-1 (DES2), or 0.4 mg·kg-1·d-1(DES3), respectively. All rats were killed after 44 weeks. The morphology of the breast tissue was observed; silver-binding nucleolar organizer regions (AgNOR) were counted; proliferating cell nuclear antigen (PCNA) staining intensity index (SII), the protein expression of Bcl-2, and C-erbB-2 were detected by SP immunohistochemistry. RESULTS: Among 15 rats with breast cancer carcinogenesis, 2 came from DES1 plus DMBA group and 13 from DMBA group. AgNOR count, and the levels of PCNA SII, Bcl-2, and C-erbB-2 were higher in DES1 group than in control group; AgNOR count, and the levels of PCNA SII, Bcl-2, and C-erbB-2 were significantly lower in DES2 plus DMBA group than in DES3 plus DMBA group and DES1 plus DMBA group (P < 0.05), but there was no significant difference between DES3 plus DMBA group and DES1 plus DMBA group (P > 0.05). CONCLUSIONS: Low dose of DES can cause hyperplasia of the mammary gland in Wistar rats but not lead to carcinogenesis. During the DMBA-induced carcinogenesis of breast cancer in Wistar rats, low dose of DES can promote the hyperplasia and carcinogenesis of the mammary gland, medium dose of DES can inhibit the proliferation of mammary epithelial cells, but the effect may weaken while increasing the dose of DES.更多还原