Establishment of breast cancer prevention protocol based on hormone milieu of pregnancy and elucidation of its molecular mechanisms

第一次足月妊娠的年龄与乳腺癌风险呈负相关。用雌激素和黄体酮短期治疗（21天或稍长的时间）可以在大鼠身上模拟怀孕对乳腺癌的保护作用。然而，目前还没有准确的评估不同时间暴露于妊娠期雌激素和孕激素水平对乳腺癌发生风险的影响。雌性Lewis大鼠在28日龄时一次性腹腔注射50 mg/kg MNU，然后不进行激素治疗（对照组），或在42日龄时皮下植入含有0.5 mg 17 β-雌二醇和32.5 mg孕酮的21天释放颗粒（E/P颗粒）。在整个实验期间，每3 ~ 4周更换一次颗粒（长期E/P组），或仅植入一次颗粒（短期组）。当大鼠出现直径大于等于1cm的乳腺肿瘤或29周龄时，处死大鼠。大鼠植入单一E/P颗粒后，循环17β -雌二醇和孕酮在植入后2周达到妊娠水平，但在植入后8周恢复到对照水平。与对照组大鼠相比，接受长期或短期E/P治疗的大鼠直径大于或等于1 cm的乳腺癌发病率降低。然而，当组织学检测到的微癌（直径<1 cm）被纳入比较时，注射MNU后22至25周，E/ p处理组的微癌数量突然增加。虽然短期E/P治疗可显著抑制各种大小的乳腺癌，但长期E/P治疗无抑癌作用。因此，E/P治疗的持续时间是抑制乳腺癌发生的重要因素。

Early age at first full-term pregnancy inversely correlates with breast cancer risk. The protective effects of pregnancy against mammary cancer can be mimicked in the rat by short-term treatment (21 days or slightly longer) with estrogen and progesterone. However, there have been no precise evaluations of the effects of different durations of exposure to pregnancy levels of estrogen and progesterone on mammary carcinogenesis risk. Female Lewis rats were administered a single intraperitoneal injection of 50 mg/kg MNU at 28 days of age, and then were either left hormone-untreated (control group), or underwent subcutaneous implantation of a 21-day release pellet containing 0.5 mg 17 β-estradiol and 32.5 mg progesterone (E/P pellet) at 42 days of age. The pellet was either replaced every 3 to 4 weeks throughout the experimental period (long-term E/P group), or was implanted only once (short-term group). The rat were sacrificed when they developed a mammary tumor with a diameter of 【greater than or equal】 1cm, or when they reached the age of 29 weeks. In rats implanted with a single E/P pellet, circulating 17β -estradiol and progesterone reached pregnancy levels 2 weeks after implantation, but returned to control levels 8 weeks after implantation. Rats that received long-or short-term E/P treatment had a decreased incidence of mammary carcinoma with a diameter of 【greater than or equal】 1 cm, compared to control rats. However, when histologically detected microcarcinomas (diameter <1 cm) were included for comparison, the E/P-treated groups exhibited an abrupt increase in the number of microcarcinomas from 22 to 25 weeks after MNU injection. Although short-term E/P treatment significantly suppressed mammary carcinomas of all sizes, long-term E/P treatment had no cancer-suppressing effect. Thus, the duration of E/P treatment is an essential factor for the suppression of mammary carcinogenesis.