Role of Vitamin D Receptor Polymorphisms in Breast Cancer

维生素 D 受体多态性在乳腺癌中的作用

• 批准号: 7555923
• 负责人: Fatouma Alimirah
• 金额: $ 3.56万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555923
• 关键词: 3' Untranslated Regions; African; African American; Age; Alleles; American Cancer Society; Apoptosis; Apoptotic; Asians; Biological Assay; Breast Cancer Cell; Breast Carcinoma; Calcitriol; Case Study; Caucasians; Caucasoid Race; Cell Differentiation process; Cell Line; Cells; Data; Development; Disease; Disease-Free Survival; Epidemiologic Studies; Epidemiology; Estrogen Receptors; Exons; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Growth; Hispanics; Human; Hypercalcemia; In Vitro; Incidence; Laboratories; Length; Link; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular; Nude Mice; Patients; Pattern; Poly A; Receptor Gene; Reporting; Retrospective Studies; Risk; Role; Signal Transduction; Survival Rate; Toxic effect; Variant; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; Woman; Xenograft Model; adenylate; analog; cancer initiation; cancer risk; cancer type; cell growth; disorder risk; malignant breast neoplasm; mortality; population based; research study; response; 3' Untranslated Regions; African; African American; Age; Alleles; American Cancer Society; Apoptosis; Apoptotic; Asians; Biological Assay; Breast Cancer Cell; Breast Carcinoma; Calcitriol; Case Study; Caucasians; Caucasoid Race; Cell Differentiation process; Cell Line; Cells; Data; Development; Disease; Disease-Free Survival; Epidemiologic Studies; Epidemiology; Estrogen Receptors; Exons; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Growth; Hispanics; Human; Hypercalcemia; In Vitro; Incidence; Laboratories; Length; Link; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular; Nude Mice; Patients; Pattern; Poly A; Receptor Gene; Reporting; Retrospective Studies; Risk; Role; Signal Transduction; Survival Rate; Toxic effect; Variant; Vitamin D; Vitamin D Analog; Vitamin D3 Receptor; Woman; Xenograft Model; adenylate; analog; cancer initiation; cancer risk; cancer type; cell growth; disorder risk; malignant breast neoplasm; mortality; population based; research study; response

DESCRIPTION (provided by applicant): African American women manifest a more aggressive form of breast cancer and have the highest mortality rate among women of Caucasian, Asian and Hispanic descent. According to a 2007 projected statistical report from the American Cancer Society, 5,830 African American women are expected to die from breast cancer alone(1-3). This ethnic bias towards the development and progression of breast cancer in African American women is not fully understood. Recent epidemiological studies have implicated genetic variations in the Vitamin D receptor (VDR) gene as the causative factors behind breast cancer initiation and progression. Specifically, case studies have linked the Fok1 VDR allelic variant in enhancing the risk of breast cancer in African American Women. Furthermore, a retrospective study revealed that this polymorphism together with another variant, the long or short Poly (A) was associated with increased risk for the disease(7). However, these findings have not been validated with experimental data. The major goal of this proposal is to elucidate the significance of VDR polymorphisms in breast cancer. To accomplish this, the following specific aims are proposed. Specific Aim 1: A. Establish expression constructs containing Fok1 allele specific VDR cDNAs with long (L) or short (s) Poly (A). B. Generate transfectants of these expression constructs in VDR-, ER-, ER+ human breast carcinoma cell lines. C. Determine the activity and function of the altered VDR gene by Dual Luciferase assay. Specific Aim 2: Identify the molecular mechanisms by which different VDR genotypes in the absence or presence of estrogen receptors modify(a) cell growth and proliferation (b) cell differentiation and in vitro invasiveness (c) apoptosis (d) VDR and ER mediated signaling in response to a less toxic Vitamin D analog, 1a(OH)D5. Specific Aim 3: Characterize the growth patterns of the transfected cells and determine their responsiveness to 1a(OH)D5 in athymic mice in a xenograft model. Relevance: The proposed study will help identify the significance of VDR polymorphism in breast cancer risk and responsiveness to Vitamin D. Importantly, the results obtained from this study may pave the way for understanding the possible role of VDR polymorphism in increased risk of breast cancer.

描述（由申请人提供）：非洲裔美国妇女表现出一种更具侵略性的乳腺癌形式，在高加索人，亚洲和西班牙裔血统的妇女中，死亡率最高。根据美国癌症协会2007年的一份统计报告，预计仅有5,830名非裔美国妇女仅因乳腺癌而死（1-3）。尚未完全了解非裔美国人妇女乳腺癌发展和发展的种族偏见。最近的流行病学研究暗示了维生素D受体（VDR）基因的遗传变异是乳腺癌启动和进展的原因。具体而言，案例研究已将FOK1 VDR等位基因变体联系起来，以增强非洲裔美国妇女的乳腺癌风险。此外，一项回顾性研究表明，这种多态性以及另一种变体长或短多（a）与疾病风险增加有关（7）。但是，这些发现尚未通过实验数据验证。该提案的主要目的是阐明VDR多态性在乳腺癌中的重要性。为此，提出了以下特定目标。特定目标1：A。建立包含长（L）或短（S）Poly（a）的FOK1等位基因特异性VDR cDNA的表达构建体。 B.在VDR-，ER-，ER+人类乳腺癌细胞系中产生这些表达构建体的转染物。 C.通过双荧光素酶测定法确定改变的VDR基因的活性和功能。具体目标2：确定在不存在或存在雌激素受体的情况下不同的VDR基因型修饰的分子机制（A）细胞生长和增殖（B）细胞分化和体外侵入性（C）凋亡（D）VDR（D）VDR和ER介导的信号响应较小的毒性维生素D Abalog，1A（OH）D5。特定目标3：表征转染细胞的生长模式，并确定其在异种移植模型中无胸腺小鼠中对1A（OH）D5的反应性。 相关性：拟议的研究将有助于确定VDR多态性在乳腺癌风险和对维生素D的反应中的重要性。重要的是，从这项研究中获得的结果可能为了解VDR多态性在增加乳腺癌风险中的可能作用铺平了道路。