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Cancer Prev Res (Phila). 2014 Mar;7(3):310-8. doi: 10.1158/1940-6207.CAPR-13-0297. Epub 2014 Jan 17.
In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ≥1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR = 1.59) or obese (HR = 1.70). To investigate this clinical observation in a preclinical setting, ovary-intact female rats were intraperitoneally injected with 50 mg/kg 1-methyl-1-nitrosourea at 21 days of age to simulate premenopausal women with increased risk. Two commercially available strains of Sprague-Dawley rat (Taconic Farms) were used, which are dietary resistant (DR) or dietary susceptible (DS) to excess weight gain when fed a purified diet containing 32% kcal from fat, similar to levels consumed by the typical American woman. DS rats were approximately 15.5% heavier than DR rats at study termination and plasma leptin indicated a marked difference in adiposity. DS rats had higher incidence (26% increase), multiplicity (2.5-fold increase), and burden (5.4-fold increase) of mammary carcinomas with a concomitant reduction in cancer latency (16% earlier detection) compared with DR rats (P < 0.001 for all analyses), and displayed a higher proportion of hormone receptor negative tumors compared with DR rats [OR = 1.78; 95% confidence interval (CI), 0.83-3.81]. Circulating levels of several breast cancer-risk factors, including leptin, adiponectin:leptin ratio, insulin, insulin-like growth factor (IGF)-1, IGF-1:IGF-1 binding protein-3 ratio, and calculated insulin resistance (HOMA-IR) were negatively impacted in DS rats (P < 0.05 for all analyses). These findings support further investigation of the effects of excess weight in high-risk premenopausal women and demonstrate a useful preclinical model for rapid evaluation of mechanistic hypotheses.
与通常报告的无效结果相反，最近有研究报道，在预防乳腺癌 P-1 试验中，高风险的绝经前妇女（Gail 评分≥1.66）超重（HR=1.59）或肥胖（HR=1.70）时乳腺癌风险增加。为了在临床前环境中研究这一临床观察结果，对 21 天大的卵巢完整雌性大鼠进行腹腔内注射 50mg/kg 的 1-甲基-1-亚硝脲，以模拟风险增加的绝经前妇女。使用了两种商业上可获得的 Sprague-Dawley 大鼠（Taconic Farms）品系，当用含有 32%脂肪卡路里的纯化饮食喂养时，它们对超重具有饮食抵抗（DR）或饮食易感性（DS），类似于典型美国女性的摄入量。DS 大鼠在研究结束时比 DR 大鼠重约 15.5%，并且血浆瘦素表明肥胖程度存在明显差异。与 DR 大鼠相比，DS 大鼠的乳腺癌发病率（增加 26%）、多发性（增加 2.5 倍）和负担（增加 5.4 倍）更高，并且癌症潜伏期（提前 16%检测到）降低（所有分析的 P<0.001），并且与 DR 大鼠相比，DS 大鼠显示出更高比例的激素受体阴性肿瘤[比值比（OR）=1.78；95%置信区间（CI），0.83-3.81]。几种乳腺癌风险因素的循环水平，包括瘦素、脂联素：瘦素比、胰岛素、胰岛素样生长因子（IGF）-1、IGF-1：IGF-1 结合蛋白-3 比和计算的胰岛素抵抗（HOMA-IR），在 DS 大鼠中受到负面影响（所有分析的 P<0.05）。这些发现支持进一步研究超重对高风险绝经前妇女的影响，并证明了一种用于快速评估机制假设的有用临床前模型。
