Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats.
Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats.
复制标题
N-甲基-N-亚硝基脲诱导的完整大鼠和卵巢切除大鼠乳腺肿瘤的生长和特征。
DOI：
10.1093/carcin/22.12.2039
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发表时间：
2001
期刊：
影响因子：
4.7
通讯作者：
Talamantes,F
中科院分区：
文献类型：
--
作者：
Thordarson,G;Lee,AV;McCarty,M;VanHorn,K;Chu,O;Chou,YC;Yang,J;Guzman,RC;Nandi,S;Talamantes,F
众所周知，大鼠中85 - 90%的化学诱导乳腺肿瘤在卵巢从动物中移除后会消失或尺寸显著减小。然而，卵巢切除术后是否有高比例的乳腺肿瘤会随着时间的延长而重新生长还不太确定。也不知道在肿瘤中基因表达发生了什么变化，因为它们发展出独立于激素的生长。本研究旨在对此进行调查。对50日龄雌性Sprague-Dawley大鼠注射N-甲基-N-亚硝基脲（MNU）50 mg/kg体重。当至少一个乳房肿瘤在一个维度上生长到1.0 - 1.5 cm时，对动物进行双侧卵巢切除术，然后监测肿瘤的缩小和再生长。对照组动物接受相同的治疗，不同的是当肿瘤出现时不切除卵巢。当对照组大鼠中的再生长和新肿瘤以及肿瘤直径达到1.0 - 1.5 cm时，将其切除，并在MNU注射后25周处死所有动物。研究中的所有动物（100%）在注射MNU后均发生乳腺肿瘤，平均潜伏期为56.5天。卵巢切除术后，93%的肿瘤大小缩小50%或更多，76%的肿瘤无法通过触诊发现。然而，在96%发生肿瘤减少或消失的动物中，发生了再生长或新的乳腺肿瘤发展，从卵巢切除术之日起平均潜伏期为52.8天。在这些卵巢切除术后肿瘤中，36%发生在卵巢切除术前肿瘤已经发展的位置，但64%出现在新的位置。卵巢切除（OVX）大鼠血清孕酮（P4）、催乳素（PRL）、生长激素（GH）和胰岛素样生长因子-I（IGF-I）浓度显著降低。来自OVX大鼠的肿瘤显示出进展的迹象，这从分化丧失和侵袭性特征中显而易见。卵巢切除大鼠和正常大鼠肿瘤的比较显示，P450芳香化酶的表达显著增加，细胞外信号调节激酶1和2的活化升高，但孕酮受体和细胞周期蛋白D1的水平降低。然而，雌激素受体（ER）含量在两组肿瘤中保持相似，至少在蛋白质水平上，IGF-I，IGF-II，胰岛素受体底物-1（IRS1），IRS-2和表皮生长因子受体的表达也是如此。IGF-I受体（IGF-IR）和ErbB-2分别在50%和70%的OVX动物肿瘤中表达，而这些基因在100%的完整大鼠肿瘤中表达。结论：化学诱导的大鼠乳腺肿瘤在卵巢切除后最初的生长可能仍然依赖于ER和E2及生长因子的局部合成。然而，随着这些肿瘤的进展，它们发展成更具侵袭性的表型，并失去对ER和可能的生长因子的依赖性。
It is well established that 85–90% of chemically induced mammary tumors in rats will disappear or diminish significantly in size after the ovaries are removed from the animal. However, it is less well established whether a high percentage of these mammary tumors will grow back with prolonged time after ovariectomy. It is also not known what changes in gene expression take place in the tumors as they develop an independence from hormones for growth. This study was carried out to investigate this. Virgin, 50-day-old female Sprague–Dawley rats were injected withN-methyl-N-nitrosourea (MNU) at the dose of 50 mg MNU/kg body wt. When at least one mammary tumor had grown to 1.0–1.5 cm in one dimension, the animal was bilaterally ovariectomized and reduction and then re-growth of the tumors monitored. Control animals were treated identically except they were not ovariectomized when tumors appeared. Re-growths and new tumors and tumors that developed in the control rats were removed when they reached 1.0–1.5 cm in diameter and all animals were killed 25 weeks after the MNU injection. All the animals in the study (100%) developed mammary tumors after MNU injection with an average latency of 56.5 days. After ovariectomy, 93% of the tumors showed 50% or more reduction in size and 76% of the tumors could not be detected by palpation. However, in 96% of the animals where tumor reduction or disappearance occurred, a re-growth or new mammary tumor development took place with an average latency period of 52.8 days from the day of ovariectomy. Of these post-ovariectomy tumors, 36% occurred at a location where tumors had developed prior to ovariectomy, but 64% appeared at new locations. The circulating levels of 17β-estradiol (E2) was undetectable in the ovariectomized (OVX) rats and significant reduction was seen in the serum concentrations of progesterone (P4), prolactin (PRL), growth hormone (GH) and insulin-like growth factor-I (IGF-I). The tumors from the OVX rats showed indications of progression as evident from loss of differentiation and invasive characteristics. Comparison between tumors from OVX and intact rats revealed a significantly increased expression of P450 aromatase and elevated activation of extracellular signal-regulated kinase 1 and 2, but reduced levels of the progesterone receptor and cyclin D1 in OVX rats. However, the estrogen receptor (ER) content remained similar in tumors from both groups, at least at the protein level, and so did the expression of IGF-I, IGF-II, insulin receptor substrate-1 (IRS1), IRS-2 and epidermal growth factor receptor. IGF-I receptor (IGF-IR) and ErbB-2 were expressed, respectively, in 50 and 70% of the tumors from the OVX animals, whereas these genes were expressed in 100% of the tumors from the intact rats. It is concluded that chemically induced rat mammary tumors may still depend on the ER and local syntheses of E2 and growth factors for growth initially after ovariectomy. However, as these tumors progress, they develop a more aggressive phenotype and lose their dependency on the ER and possibly growth factors.