Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments.
Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments.
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生长激素缺乏的自发性侏儒大鼠乳腺肿瘤的发生；
DOI：
10.1007/s10549-004-9504-2
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Talamantes,Frank
中科院分区：
文献类型：
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作者：
Thordarson,Gudmundur;Semaan,Sheila;Low,Caroline;Ochoa,Dafne;Leong,Harriet;Rajkumar,Lakshmanaswamy;Guzman,RaphaelC;Nandi,Satyabrata;Talamantes,Frank
本研究旨在探讨生长激素（GH）缺乏的自发性侏儒大鼠（SDR）乳腺肿瘤的发生。在50-60日龄时，将大鼠分为5组。第1组接受牛（B）GH（缓释制剂），剂量为40-50 mg/kg体重。每周注射50 μl;第2组接受重组人胰岛素样生长因子-I（IGF-I），剂量为1 mg/kg体重/d。第3组动物皮下植入含30 μg 17β-雌二醇（E2）和30 mg孕酮（P4）的硅橡胶胶囊，每2个月更换一次;第4组动物接受与上述相同剂量的bGH和E2 + P4治疗，对照组动物（第5组）接受假治疗（植物油注射，含纤维素的硅橡胶胶囊）。给药1周后，所有动物腹腔注射致癌剂N-甲基-N-亚硝基脲（MNU），剂量为50 mg/kg体重。接受与暴露于MNU的动物相同的激素治疗的其他动物组仅治疗10天，然后处死，以评估致癌物暴露时激素的循环浓度和乳腺特征。暴露于MNU的动物的激素治疗再持续20周，通过每周触诊监测乳腺肿瘤发展，必要时收集肿瘤。每周对大鼠称重。在处理期结束时，处死所有动物并收集剩余肿瘤。在整个实验期间，所有组中的大鼠体重持续增加，但在单独接受GH或接受GH与E2和P4的动物中观察到最大的体重增加。与对照组相比，接受IGF-I治疗的动物体重也有所增加，但这种体重增加低于GH治疗大鼠。GH单独治疗使乳腺肿瘤发生率从对照组的4.8%增加至100%。GH处理大鼠的平均肿瘤负荷和潜伏期分别为7.0 ± 0.8个肿瘤/荷瘤大鼠（平均值±SEM）和57.3 ± 2.7天（平均值±SEM）。与完整的Sprague-Dawley大鼠一样，GH处理大鼠中约90%的肿瘤生长依赖于卵巢。IGF-I治疗还将乳腺肿瘤的发展增加至62.5%。IGF-I处理大鼠的平均肿瘤负荷和潜伏期分别为1.6 ± 0.4个肿瘤/荷瘤大鼠（平均值±SEM）和96.2 ± 14.5天（平均值±SEM）。然而，E2+P4治疗没有显着改变肿瘤发生，令人惊讶的是，同时治疗E2+P4和GH消除GH刺激的肿瘤发展的增加。催乳素（PRL）似乎没有影响乳腺肿瘤的SDR，作为未处理的SDR有显着升高血清中的PRL浓度相比，正常的SD大鼠，而GH处理的SDR的PRL水平与正常SD大鼠。没有明显的结构特征与乳腺肿瘤发生的高或低的易感性，评估乳腺全坐骑从不同的动物组在致癌剂administration. Enhancement细胞外信号调节激酶1/2（ERK 1/2）的表达增强，和激活（磷酸化）的ERK 1/2与乳腺肿瘤发生的增加。同样，雌激素受体-α（ERα）的表达在肿瘤发生易感性最高的动物组中显著升高，而细胞周期蛋白D1的表达水平与乳腺肿瘤发生无关。
This study was carried out to investigate mammary tumorigenesis in growth hormone (GH) deficient spontaneous dwarf rats (SDR). At 50–60 days of age, the rats were divided into five groups. Group 1 received bovine (b) GH (prolonged release formulation) administered at a dose of 40–50 mg/kg body wt. in 50 μl weekly injections; group 2 received recombinant human insulin-like growth factor-I (IGF-I) at a dose of 1 mg/kg body wt./day administered via osmotic pumps; animals in group 3 were fitted with subcutaneous silastic capsule containing 30 μg 17β-estradiol (E2) plus 30 mg progesterone (P4), replaced every 2 months; group 4 received both bGH and E2 plus P4 treatments at the same doses as above, and control animals (group 5) received sham treatments (vegetable oil injection, silastic capsules containing cellulose). After 1week of treatment, all animals were injected intraperitoneally with the carcinogenN-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg body wt. Other groups of animals, receiving identical hormonal treatment to those exposed to MNU, were treated for 10 days only and then sacrificed for assessment of circulating concentrations of hormones and mammary gland characteristics at the time of carcinogen exposure. The hormonal treatments of the animals exposed to the MNU were continued for an additional 20 weeks and mammary tumor development monitored by weekly palpation and tumors collected as necessary. The rats were weighed weekly. At the end of the treatment period, all animals were sacrificed and remaining tumors were collected. Rats in all groups continued to gain weight throughout the experimental period, but the largest weight gain was see in animals receiving GH either alone or with E2 and P4. Animals treated with IGF-I also gained weight compared to controls, but this weight gain was less than that seen in GH-treated rats. GH treatment alone increased mammary tumor incidence from 4.8% in controls to 100%. Average tumor load and latency in the GH-treated rats were 7.0 ± 0.8 tumors/tumor-bearing rat (mean±SEM) and 57.3 ± 2.7 days (mean±SEM), respectively. As in intact Sprague–Dawley rats, approximately 90% of the tumors that developed in the GH-treated rats were ovarian dependent for growth. IGF-I treatment also increased mammary tumor development to 62.5%. Average tumor load and latency in the IGF-I-treated rats were 1.6 ± 0.4 tumors/tumor-bearing rat (mean±SEM) and 96.2 ± 14.5 days (mean±SEM), respectively. However E2+P4 treatments did not significantly alter tumorigenesis and, surprisingly, simultaneous treatment with E2+P4 and GH obliterated the GH-stimulated increase in tumor development. Prolactin (PRL) did not appear to influence mammary tumorigenesis in the SDRs, as untreated SDRs had significantly elevated serum concentration of PRL as compared with normal Sprague–Dawley (SD) rats, whereas GH-treated SDRs had PRL levels similar to that of normal SD rats. No obvious structural characteristics were associated with high or low susceptibility to mammary tumorigenesis, as assessed by mammary gland whole mounts from the different animal groups sacrificed at the time of carcinogen administration.Enhanced expression of the extracellular signal-regulated kinase 1/2 (ERK1/2), and activation (phosphorylation) of ERK1/2 were associated with an increase in mammary tumorigenesis. Similarly, the expression of the estrogen receptor-α(ERα) was significantly elevated in animal groups with the highest susceptibility to tumorigenesis, whereas the levels of cyclin D1 expression were not related to mammary tumorigenesis.