Sex Hormones, Phytoestrogens and Lung Cancer in Female Nonsmokers

 描述（由申请人提供）：肺癌是女性癌症死亡的主要原因。虽然吸烟已被确定为主要风险因素，但据估计，全世界53%的女性肺癌病例是非吸烟者。非吸烟者肺癌的病因仍然知之甚少。在两项大型临床试验中，绝经后激素替代疗法（HRT）已被证明会增加发生侵袭性肺癌的风险和肺癌死亡率，而使用抗雌激素他莫昔芬与肺癌死亡风险降低相关。提示雌激素可能在肺癌发生中起重要作用。然而，迄今为止还没有研究直接评估内源性雌激素与肺癌风险之间的关系。另一方面，大豆植物雌激素，结构上类似于哺乳动物雌激素，具有抗雌激素活性。我们最近在一项试点研究中发现，大豆食品摄入量与肺癌风险和死亡率显著负相关。我们还发现，在一项小型试点研究中，两种大豆异黄酮染料木素和黄豆黄素的尿液水平较高与肺癌风险较低相关，并且这种倒置相关性在侵袭性肺癌中更为明显。这些发现与临床试验中使用HRT的肺癌风险和死亡率显著增加的发现形成直接对比。这些发现虽然是初步的，但提供了强有力的证据。 支持一种新的假说，即大豆异黄酮，可能通过其抗雌激素活性等机制，可能有利地影响肺癌的发展和进展。我们建议在这个应用程序中，以评估潜在的作用，内源性激素和饮食中的植物雌激素在肺癌的病因，在女性非吸烟者。这项研究将建立在上海妇女健康研究（SWHS）的基础上，该研究是一项前瞻性队列研究，共有74，941名中国妇女参加。具体来说，我们建议进行巢式病例对照研究的660例肺癌的发病病例和他们的个人匹配的控制在非吸烟绝经后妇女。将使用基于液相色谱-质谱法的方法，测量基线时采集的样本中的血浆性激素和尿睾酮。此外，我们将研究大豆植物雌激素摄入量与肺癌风险和死亡率的关系。SWHS代表了一个特殊的机会，以解决这些有针对性的问题，因为它的大尺寸，前瞻性设计，高随访率，以及尿液和血液样本的可用性。更重要的是，它提供了重复的饮食评估和一个独特的研究人群，烟草产品和HRT使用的患病率极低，但大豆食品的摄入量范围很广。从拟议的研究结果将填补重要的空白，我们的知识的作用，内源性雌激素和饮食中的植物雌激素暴露在肺癌的病因，并可能有助于发展新的战略，对这种致命的疾病。

 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in women. Although cigarette smoking has been established as the principal risk factor, an estimated 53% of female lung cancer cases worldwide are nonsmokers. The etiology of lung cancer in nonsmokers remains poorly understood. Postmenopausal hormone replacement therapy (HRT) has been shown to increase the risk of developing aggressive lung cancer and lung cancer mortality in two large clinical trials, whereas use of anti-estrogen tamoxifen is associated with a reduced risk of lung cancer death. These findings indicate that estrogens may play an important role in lung carcinogenesis. No study to date, however, has directly evaluated the association between endogenous estrogens and lung cancer risk. On the other hand, soy phytoestrogens, structurally similar to mammalian estrogens, possess anti- estrogenic activities. We recently found in a pilot study that soy food intake was significantly and inversely associated with both lung cancer risk and mortality. We also found that higher urinary levels of two soy isoflavones genistein and glycitein were associated with a lower risk of lung cancer in a small pilot study, and the inversion association was more pronounced for aggressive lung cancer. These findings are in direct contrast to the finding of a significant increase in lung cancer risk and mortality with HRT use in clinical trials. These findings, although preliminary, provide strong support for a novel hypothesis that soy isoflavones, possibly through their anti-estrogenic activities among other mechanisms, may favorably influence the development and progression of lung cancer. We propose in this application to evaluate the potential role of endogenous sex hormones and dietary phytoestrogens in the etiology of lung cancer in female nonsmokers. The proposed study will build upon the Shanghai Women's Health Study (SWHS), a prospective cohort of 74,941 Chinese women. Specifically, we propose to conduct a nested case-control study of 660 incident cases of lung cancer and their individually matched controls in nonsmoking postmenopausal women. Plasma sex hormones and urinary isoflavonoids will be measured in samples collected at baseline using liquid chromatography mass spectrometry based methods. In addition, we will examine the association of soy phytoestrogen intake with lung cancer risk and mortality in the full cohort. The SWHS represents an exceptional opportunity to address such targeted questions given its large size, prospective design, high follow-up rate, and availability of both urine and blood samples. More importantly, it provides repeated dietary assessments and a unique study population with an extremely low prevalence of tobacco product and HRT use but a wide range of soy food intake. Results from the proposed study will fill important gaps in our knowledge regarding the role of endogenous estrogen and dietary phytoestrogen exposure in the etiology of lung cancer and potentially contribute to the development of new strategies against this fatal disease.