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，表明对癌症具有保护作用。编码维生素D的活性代谢物1，25（OH）2D的形成和降解的酶存在于正常和癌症乳腺细胞中，维生素D受体也是维生素D途径中的关键介质。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，前瞻性数据很少。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，因为它捕获了肠道中维生素D的吸收及其在皮肤中的产生。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是否改变循环雌二醇与绝经后妇女乳腺癌风险的相关性。该研究将是一项病例对照研究，嵌套在两个队列中，纽约大学妇女健康研究和瑞典的乳腺癌筛查队列。这两个队列具有相似的设计，并前瞻性地收集生物样本。预计在这两个队列中将观察到总共1 995例事件。将为每例病例选择一个（或对于<52岁的病例选择两个）对照，在队列、人种/种族、绝经状态、献血时的年龄和日期方面与病例匹配。除了基线测量外，我们还将在大约50%的匹配组中的重复时间点评估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（CYP 27 A1，CYP 24 A1，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联合影响。将在绝经后匹配集中测量雌二醇的循环水平。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）不容易改变。相比之下，如果维生素D被证明对乳腺癌有保护作用，那么通过无毒且廉价的补充剂就可以很容易地改变维生素D的水平。由于相当一部分美国人的维生素D水平低于最佳水平，因此预防乳腺癌的潜力很大。

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.