GENETIC ABNORMALITIES EARLY ON THE PATH OF BREAST CANCER

乳腺癌早期的遗传异常

• 批准号: 6729944
• 负责人: CAROL L ROSENBERG
• 金额: $ 21.26万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729944
• 关键词: alleles; brca gene; breast neoplasms; carcinogenesis; clinical research; cyclin dependent kinase; enzyme inhibitors; female; gene mutation; human subject; immunocytochemistry; loss of heterozygosity; neoplasm /cancer genetics; patient oriented research; women' s health

DESCRIPTION: Breast cancer is a genetic disease, but little is known about genetic abnormalities central to the first steps of tumorigenesis. Identifying these abnormalities may be critical to understand breast cancer risk and development, and to create new detection and treatment strategies. To elucidate these important early abnormalities, Dr. Rosenberg and colleagues developed a powerful system using microsatellite markers to investigate archival specimens of human breast tissue. It was demonstrated that "benign" and even histologically normal breast tissue could contain monoclonal, genetically aberrant cell populations. Based on these studies, it has been hypothesized, first, that breasts of certain individuals may contain widespread genetic abnormalities, i.e., field cancerization. To test this hypothesis, this research team will examine normal-appearing breast tissue from 2 groups at risk for a field defect: 1) premenopausal women with sporadic breast cancer; and 2) premenopausal women with a heritable, constitutional mutation in BRCA1 or BRCA2 genes. Dr. Rosenberg speculates that these tissues will contain an increase in genetic abnormalities, especially allele imbalance (AI) suggestive of loss of heterozygosity (LOH), compared with control reduction mammoplasty (RM) specimens. Further, the patterns of abnormalities in the groups may differ, suggesting distinct pathways of carcinogenesis. Second, it is hypothesized that sites of frequent LOH in histologically normal breast epithelium may identify candidate genes critical to the earliest stages of breast tumorigenesis. Candidate genes to be tested must fulfill tow criteria: 1) location near frequent sites of LOH in normal-appearing tissue (likely indicating the existence of a tumor-suppressor gene in the vicinity) and 2) a role in carcinogenesis, maintenance of genomic stability, or growth control documented in the literature. To test their potential role in breast carcinogenesis, Dr. Rosenberg will then examine these genes' expression in normal-appearing, proliferative and malignant breast tissue. Pilot studies identified the first, paradigmatic, example of this strategy: p57KIP2, a cyclin dependent kinase inhibitor (CDKI) which inhibits cyclin/cdk complexes and arrests cells in G1. To test this hypothesis, three aims are proposed. Aim 1 is to determine whether field cancerization exists in histologically normal breast epithelium of women less than 40 years of age with sporadic breast cancer or with heritable, constitutional BRCA1 or BRCA2 mutations, compared to control tissue. Aim 2 is to identify candidate genes acting early in breast carcinogenesis. Aim 3 is to test candidate genes to determine if their inactivation contributes to the transition from normal to transformed breast epithelial cells. Studies are outlined with the first identified candidate, p57KIP2. These investigations should illuminate genetic events instrumental in the initial steps of breast carcinogenesis.

描述：乳腺癌是一种遗传疾病，但对 遗传异常是肿瘤发生的第一步的中心。识别 这些异常对于了解乳腺癌风险和 开发并创建新的检测和治疗策略。阐明 这些重要的早期异常，Rosenberg博士及其同事开发了 使用微卫星标记来研究档案标本的强大系统 人类乳腺组织。已经证明了“良性”，甚至 组织学上正常的乳腺组织可能含有单克隆的遗传学 异常细胞群体。基于这些研究，已经假设 首先，某些人的乳房可能包含广泛的遗传 异常，即场癌。为了检验这一假设， 研究小组将检查来自2组风险的两组的正常表现乳腺组织 对于现场缺陷：1）绝经前妇女患有零星乳腺癌；和2） 绝经前妇女在BRCA1或BRCA2中具有遗传性的宪法突变 基因。罗森伯格博士推测这些组织将包含增加 遗传异常，尤其是等位基因失衡（AI） 与对照减少乳腺成形术（RM）相比，杂合性（LOH） 标本。此外，组中异常的模式可能有所不同， 提出了癌变的不同途径。其次，假设 在组织学正常乳房上皮中频繁的LOH的位置可能会识别 候选基因对乳腺肿瘤最早的最早阶段至关重要。 要测试的候选基因必须满足拖曳标准：1）位置附近 在正常表现组织中频繁的LOH位点（可能表明 在附近存在肿瘤抑制基因）和2） 癌变，基因组稳定性的维持或已记录的生长控制 在文献中。为了测试其在乳腺癌发生中的潜在作用，博士 然后，罗森伯格将检查这些基因在正常表现中的表达， 增殖和恶性乳腺组织。试点研究确定了第一个 范式，此策略的示例：p57kip2，一种依赖细胞周期蛋白激酶 抑制剂（CDKI）抑制细胞周期蛋白/CDK复合物并阻止G1中的细胞。 为了检验这一假设，提出了三个目标。目标1是确定是否 妇女的组织学正常乳房上皮存在现场癌化 零星乳腺癌或可遗传的年龄不到40岁 与对照组织相比，宪法BRCA1或BRCA2突变。 AIM 2是 确定在乳腺癌作用早期作用的候选基因。目标3是 测试候选基因以确定其失活是否有助于 从正常到转化的乳腺上皮细胞的过渡。研究是 概述了第一个确定的候选人P57KIP2。这些调查 应该照亮遗传事件在乳房的初始步骤中发挥作用 致癌作用。

项目成果

CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer.

• DOI: 10.1186/1471-2407-8-68
• 发表时间: 2008-03-06
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Larson PS;Schlechter BL;King CL;Yang Q;Glass CN;Mack C;Pistey R;de Las Morenas A;Rosenberg CL
• 通讯作者: Rosenberg CL