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

首次足月妊娠的早期年龄与乳腺癌风险呈负相关。通过短期（21天或稍长时间）给予雌激素和孕激素，可以在大鼠中模拟妊娠对乳腺癌的保护作用。然而，一直没有精确的评估，不同的持续时间暴露于怀孕水平的雌激素和孕激素对乳腺癌的风险的影响。雌性刘易斯大鼠在28日龄时单次腹腔注射50 mg/kg MNU，然后不给药（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至4周更换一次颗粒（长期E/P组），或仅植入一次（短期组）。当大鼠出现直径[大于或等于] 1cm的乳腺肿瘤时，或当它们达到29周龄时，将其处死。在植入单个E/P颗粒的大鼠中，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小癌（直径<1 cm）进行比较时，E/P处理组在MNU注射后22至25周表现出微小癌数量的突然增加。虽然短期E/P治疗显着抑制各种大小的乳腺癌，长期E/P治疗没有抑癌效果。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.