The IGF Signaling Pathway and Breast Cancer Risk

IGF 信号通路与乳腺癌风险

• 批准号: 7373525
• 负责人: Susan L. Neuhausen
• 金额: $ 52.56万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-12 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373525
• 关键词: Address; Affect; African American; Age; Area; Asian Americans; Biological Models; Body mass index; CTSD gene; Cancer Etiology; Caucasians; Caucasoid Race; Cell Proliferation Regulation; Codon Nucleotides; DNA Resequencing; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; ESR1 gene; ESR2 gene; Environment; Epidemiologic Studies; Epidemiological Factors; Estrogens; Etiology; Exogenous Hormone Therapy; Family; Family-Based Registry; Female; Foundations; Functional RNA; Genes; Genetic; Genetic Epistasis; Genetic Variation; Genotype; Haplotypes; Hereditary Breast Carcinoma; Hispanics; IGF1 gene; IGF1R gene; IGF2 gene; IGF2R gene; IGFBP1 gene; IGFBP2 gene; IGFBP3 gene; IGFBP4 gene; IGFBP5 gene; IGFBP6 gene; INSR gene; IRS1 gene; IRS2 gene; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor Binding Protein 1; Introns; KLK3 gene; Linkage Disequilibrium; MMP3 gene; Malignant Neoplasms; Menopausal Status; Modeling; Morbidity - disease rate; Numbers; Outcome; Pathway interactions; Personal Satisfaction; Pharmaceutical Preparations; Physical activity; Play; Population; Premenopause; Prevention; Prevention strategy; Process; Prostate-Specific Antigen; Research; Resources; Risk; Risk Assessment; Role; SHBG gene; SHC1 gene; Serum; Siblings; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Sister; Somatomedins; Staging; Stromelysin 1; Tumor stage; Variant; Woman; Women' s Group; anticancer research; base; breast cancer family; cancer risk; case control; case-based; cell growth; chemotherapy; design; genetic risk factor; genetic variant; human IRS2 protein; human SHC1 protein; insulin receptor substrate 1 protein; malignant breast neoplasm; mortality; uncontrolled cell growth; validation studies

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer among women, with significant morbidity and mortality. We hypothesize that variation in genes involved in insulin-like growth factor (IGF) signaling play a key role in breast cancer etiology. The IGF pathway regulates cell growth, and as uncontrolled cell growth is a hallmark of cancer, this pathway is a key component. We propose a comprehensive analysis of genes involved in IGF signaling through an approach that combines multiple variants in a single gene to form haplotypes and examines interactions of multiple genes in this important pathway. To investigate these associations, we will employ a two-stage approach. In the first stage, we will identify genetic variants significantly associated with breast cancer in a family-based association design of women with breast cancer and their unaffected female siblings, using existing resources of the Breast CFR and the kConFab. In the second stage, we will validate associations identified from the family-based design in a case-control design of population-based cases and controls. Our specific aims are: Aim 1 .To identify Single Nucleotide Polymorphisms (SNPs) in genes involved in IGF signaling and determine the haplotype tagging SNPs for genotyping that will maximize genetic information. Aim 2.To genotype SNPs selected in Aim 1 in the Caucasian breast cancer sibships. There are 2420 affecteds (cases) and 3118 unaffecteds (controls) in 3576 discordant sibling pairs (2126 sibships). Aim 3. To evaluate the association of haplotypes and SNPs in genes involved in IGF signaling and risk of breast cancer and age at diagnosis. We will analyze main effects, gene x gene interactions and gene x environment interactions. Epidemiological factors will include menopausal status, body mass index, physical activity, and exogenous hormone use. Aim 4.To validate significant associations of SNPs and haplotypes with breast cancer risk identified in Aim 3 using a set of 1900 Caucasian population-based cases and 1900 age-matched controls. We will further explore validated SNPs and haplotypes in African-American, Asian-American, and Hispanic discordant sibships. This study will address a critical and yet largely under-evaluated area in breast cancer research - the identification of genetic risk factors in a pathway central to the regulation of cell proliferation, a process underlying the development and progression of breast cancer. These results will provide information to more accurately assess breast cancer risk in women and to target women who could benefit from prevention strategies. Currently, chemotherapies are being directed to the IGF pathway and the results of this study could provide further targets, as well as assist in identifying the group of women who could particularly benefit from these new drugs.

描述（由申请人提供）：乳腺癌是女性中最常见的癌症，具有显著的发病率和死亡率。我们推测，参与胰岛素样生长因子（IGF）信号转导的基因变异在乳腺癌病因中起着关键作用。IGF途径调节细胞生长，由于不受控制的细胞生长是癌症的标志，因此该途径是关键组成部分。我们提出了一个全面的分析基因参与IGF信号通过一种方法，在一个单一的基因，形成单倍型，并检查多个基因在这一重要途径的相互作用相结合的多个变体。为了研究这些关联，我们将采用两个阶段的方法。在第一阶段，我们将使用乳腺CFR和kConFab的现有资源，在乳腺癌女性及其未受影响的女性同胞的基于家庭的关联设计中识别与乳腺癌显著相关的遗传变异。在第二阶段，我们将在基于人群的病例和对照的病例对照设计中验证从基于家系的设计中识别的关联。我们的具体目标是：目的1 .鉴定IGF信号转导相关基因的单核苷酸多态性（SNPs），并确定单倍型标记SNPs用于基因分型，以最大化遗传信息。目的2.在高加索人乳腺癌同胞中对Aim 1中选择的SNPs进行基因分型。在3576对不和谐同胞对（2126个同胞）中，有2420例患病（病例）和3118例未患病（对照）。目标3.评估IGF信号转导相关基因的单倍型和SNP与乳腺癌风险和诊断年龄的相关性。我们将分析主效应，基因x基因交互作用和基因x环境交互作用。流行病学因素包括绝经状态、体重指数、体力活动和外源性激素的使用。目的4：使用一组1900例白人人群病例和1900例年龄匹配的对照，验证单核苷酸多态性和单倍型与目的3中确定的乳腺癌风险的显著相关性。我们将进一步探讨非裔美国人、亚裔美国人和西班牙裔美国人不一致亲缘关系中经过验证的SNP和单倍型。这项研究将解决乳腺癌研究中的一个关键但在很大程度上被低估的领域-识别细胞增殖调节途径中的遗传风险因素，这是乳腺癌发展和进展的基础过程。这些结果将为更准确地评估女性乳腺癌风险提供信息，并针对可能从预防策略中受益的女性。目前，化疗正在针对IGF途径，这项研究的结果可以提供进一步的目标，并有助于确定特别受益于这些新药的妇女群体。