Vitamin D, Related Genes and Breast Cancer Risk

描述（由研究者提供）：大量实验数据表明，维生素D抑制细胞增殖，诱导分化和凋亡，提示对癌症有保护作用。编码1225 (OH)2D（维生素D的活性代谢物）形成和降解的酶存在于正常和癌乳腺细胞中，维生素D受体也是维生素D途径的关键介质。生态学和病例对照研究支持维生素D对乳腺癌的保护作用；然而，未来的数据是稀疏的。此外，很少有研究测量循环25(OH)D，这被认为是维生素D状态的最佳指标，因为它既能捕捉肠道对维生素D的吸收，也能捕捉皮肤对维生素D的产生。我们建议对维生素D途径与乳腺癌风险的关系进行全面研究。由于维生素D影响细胞增殖，这是雌激素增加乳腺癌风险的主要机制，我们还将评估维生素D是否会改变绝经后妇女循环雌二醇与乳腺癌风险的关系。该研究将是一个病例对照研究，嵌套在两个队列中，纽约大学妇女健康研究和瑞典的乳房筛查队列。这两个队列具有相似的设计，并前瞻性地收集生物样本。在这两个队列中预计总共观察到1 995个事件病例。将为每个病例选择一个（或两个）对照，在队列、种族/民族、绝经状态、年龄和献血日期方面与病例相匹配。除了基线测量外，我们将在大约50%的匹配集的重复时间点评估25(OH)D（25%的2个样本和25%的3个样本）。我们还将评估维生素D相关基因（CYP27A1、CYP24A1、DBP、VDR和RXRA）的遗传变异，并评估循环25(OH)D和这些基因变异对乳腺癌风险的共同影响。在绝经后配对组中测量循环雌二醇水平。公共卫生相关性：乳腺癌是美国女性发病率最高的癌症。大多数已知的乳腺癌风险因素（遗传和生殖）是不容易改变的。相比之下，如果维生素D被证明可以预防乳腺癌，那么它的含量很容易通过无毒和廉价的补充剂来改变。由于相当一部分美国人的维生素D含量低于理想水平，因此预防乳腺癌的可能性很大。

DESCRIPTION (provided by investigator): A large body of experimental data indicates that vitamin D inhibits cellular proliferation and induces differentiation and apoptosis, suggesting a protective effect against cancer. The enzymes coding for the formation and degradation of 1,25(OH)2D, the active metabolite of vitamin D, are present in both normal and cancer breast cells, as is the vitamin D receptor, a key mediator in the vitamin D pathway. Ecological and case- control studies support a protective role of vitamin D against breast cancer; however, prospective data are sparse. Moreover, few studies have measured circulating 25(OH)D which is considered the best indicator of vitamin D status because it captures both the absorption of vitamin D in the intestine and its production in the skin. We propose to conduct a comprehensive study of the vitamin D pathway in relation to breast cancer risk. Because vitamin D impacts cell proliferation, the main mechanism by which estrogens increase breast cancer risk, we will also assess whether vitamin D modifies the association of circulating estradiol with breast cancer risk in postmenopausal women. The study will be a case-control study nested within two cohorts, the NYU Women's Health Study and the Mammary Screening Cohort in Sweden. These two cohorts have a similar design and collected biological samples prospectively. A total of 1,995 incident cases is expected to be observed within these two cohorts. One (or two for cases d 52 years of age) control(s) will be selected for each case, matching the case on cohort, race/ethnicity, menopausal status, age at, and date of, blood donation. In addition to baseline measurements, we will assess 25(OH)D at repeat points in time in about 50 percent of the matched sets (2 samples in 25 percent and 3 samples in 25 percent). We will also assess genetic variation in vitamin D-related genes (CYP27A1, CYP24A1, DBP, VDR, and RXRA) and evaluate the joint effects of circulating 25(OH)D and variants in these genes on breast cancer risk. Circulating levels of estradiol will be measured in postmenopausal matched sets. PUBLIC HEALTH RELEVANCE: Breast cancer is the cancer with highest incidence in women in the US. Most of the known risk factors for breast cancer (genetic and reproductive) are not readily modifiable. By contrast, if vitamin D proves to be protective against breast cancer, levels are readily modifiable through supplements which are nontoxic and inexpensive. Since a significant fraction of the American population has suboptimal levels of vitamin D, there would be a large potential for breast cancer prevention.