Swanson S M, Whitaker L M, Stockard C R, Myers R B, Oelschlager D, Grizzle W E, Juliana M M, Grubbs C J
Department of Nutrition Sciences, University of Alabama at Birmingham 35294, USA.
Anticancer Res. 1997 Nov-Dec;17(6D):4639-45.
Women who bear their first child by their late teens have about half the risk of developing breast cancer relative to nulliparous women. The rat is a good model for studying the role of hormones in breast cancer since, for example, young rats become nearly refractory to mammary carcinogenesis after delivering a litter of pups. Short term administration of estradiol and progesterone (E & P) provides virgin rats protection from mammary carcinogenesis as effectively as pregnancy. The purpose of these studies were twofold: first, to evaluate potential long-term toxicity of the E & P treatments and second, to compare hormone treated rats and pregnant rats with respect to circulating E & P levels as well as mammary epithelial cell proliferation and differentiation. To test for toxicity, rats were treated with E & P (20 micrograms and 4 mg, respectively) or vehicle by s.c. injections 5 times per week for 5 weeks beginning at 40 days of age. The animals were weighed biweekly and sacrificed at 500 days of age when detailed necropsies were performed. No significant difference in weight gain was observed between the two groups nor was any toxicity grossly observable in the hormone-treated rats. Furthermore, there was no increase in the number of spontaneous mammary or pituitary tumors in the E & P treated group relative to controls. To evaluate serum hormone titers and mammary proliferation, rats were treated with steroids or vehicle daily beginning at 65 days of age. At 6 and 24 hours after the 1st, 14th and 35th injection, serum E & P were measured by RIA and mammary epithelial cell proliferation by immunohistochemistry (PCNA). At 6 hours after each injection, E & P levels were 3 to 5 fold those observed late in pregnancy. By 24 hours, however, E & P levels subsided to late pregnancy levels or lower. The mammary epithelial cell proliferation index in either E & P treated or late pregnant rats was 6 to 14%. Histologic sections and wholemounts of mammary glands showed a similar degree of differentiation between rats treated with E & P for 14 days or longer and late pregnant rats. These data further suggest that E & P treatments are a non-toxic means of mimicking the protective effect of pregnancy against mammary cancer and that pregnancy or hormone treatments may achieve this prophylaxis through a differentiation mechanism.
相对于未生育的女性，在接近二十岁时生育第一胎的女性患乳腺癌的风险大约减半。大鼠是研究激素在乳腺癌中作用的良好模型，例如，年轻大鼠在产下一窝幼崽后对乳腺癌变几乎具有抗性。短期给予雌二醇和孕酮（E&P）能像怀孕一样有效地为未生育的大鼠提供预防乳腺癌变的保护。这些研究的目的有两个：第一，评估E&P治疗的潜在长期毒性；第二，比较激素处理的大鼠和怀孕大鼠在循环E&P水平、乳腺上皮细胞增殖和分化方面的情况。为了测试毒性，从40日龄开始，大鼠每周皮下注射5次E&P（分别为20微克和4毫克）或赋形剂，持续5周。每两周称一次动物体重，并在500日龄时处死，进行详细的尸检。两组之间在体重增加方面没有观察到显著差异，在激素处理的大鼠中也没有明显观察到任何毒性。此外，与对照组相比，E&P处理组的自发性乳腺或垂体肿瘤数量没有增加。为了评估血清激素滴度和乳腺增殖情况，从65日龄开始，大鼠每天接受类固醇或赋形剂处理。在第1次、第14次和第35次注射后的6小时和24小时，通过放射免疫分析（RIA）测量血清E&P，通过免疫组织化学（PCNA）测量乳腺上皮细胞增殖。每次注射后6小时，E&P水平是妊娠后期观察到水平的3至5倍。然而，到24小时时，E&P水平降至妊娠后期水平或更低。E&P处理的大鼠或妊娠后期大鼠的乳腺上皮细胞增殖指数为6%至14%。乳腺组织切片和整装片显示，接受E&P处理14天或更长时间的大鼠与妊娠后期大鼠之间的分化程度相似。这些数据进一步表明，E&P处理是模拟怀孕对乳腺癌预防作用的一种无毒方法，并且怀孕或激素处理可能通过分化机制实现这种预防。
