Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
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DOI：
10.1093/jnci/djn415
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发表时间：
2009-01-07
影响因子：
10.3
通讯作者：
Strickler, Howard D.
中科院分区：
文献类型：
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作者：
Gunter, Marc J.;Hoover, Donald R.;Strickler, Howard D.
肥胖与绝经后乳腺癌之间的正相关部分归因于雌激素（乳腺癌的危险因素）是在脂肪组织中合成的。肥胖还与高水平的胰岛素（一种已知的有丝分裂原）有关。然而，还没有前瞻性研究直接评估胰岛素和/或胰岛素样生长因子 (IGF)-I（一种相关激素）的循环水平与独立于雌激素水平的乳腺癌风险之间的关联。我们对参加妇女健康倡议观察性研究 (WHI-OS) 的非糖尿病女性进行了一项病例队列研究，该研究是一个由 93 676 名绝经后妇女组成的前瞻性队列。研究开始时，对 835 名乳腺癌病例受试者和 816 名随机选择的 WHI-OS 受试者亚组中获得的空腹血清样本进行了胰岛素、葡萄糖、总 IGF-I、游离 IGF-I、胰岛素样生长因子结合蛋白 3 和雌二醇水平的检测。使用多变量 Cox 比例风险模型来估计血清学因素水平和基线特征（包括体重指数 [BMI]）与乳腺癌风险之间的关联。所有统计检验都是双向的。胰岛素水平与乳腺癌风险呈正相关（胰岛素水平最高与最低四分位数的风险比 [HR] = 1.46，95% 置信区间 [CI] = 1.00 至 2.13，P 趋势 = .02）；然而，与胰岛素水平的关联因激素治疗 (HT) 的使用而异（P 交互作用 = 0.01）。在控制包括雌二醇在内的多种乳腺癌危险因素的模型中，仅在非 HT 使用者中，胰岛素水平与乳腺癌相关（胰岛素水平最高与最低四分位数的 HR = 2.40，95% CI = 1.30 至 4.41，P 趋势 < .001）。肥胖（BMI >= 30 kg/m(2)）也与非 HT 使用者患乳腺癌的风险相关（BMI >= 30 kg/m(2) 的 HR 与 18.5 至 < 25 kg/m(2) = 2.12，95% CI = 1.26 至 3.58，P 趋势 = .003）；然而，这种关联因胰岛素调整而减弱（P-趋势 = .40）。这些数据表明，高胰岛素血症是乳腺癌的独立危险因素，并且可能在解释肥胖与乳腺癌的关系中发挥重要作用。
The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93 676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided.Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, P-trend = .02); however, the association with insulin level varied by hormone therapy (HT) use (P-interaction = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, P-trend < .001). Obesity (BMI >= 30 kg/m(2)) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI >= 30 kg/m(2) vs 18.5 to < 25 kg/m(2) = 2.12, 95% CI = 1.26 to 3.58, P-trend = .003); however, this association was attenuated by adjustment for insulin (P-trend = .40).These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.