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Mammary Gland Laterality in Normal and Neoplastic Development

正常和肿瘤发育中的乳腺偏侧性

基本信息

批准号：
8241938
负责人：
ANN F RAMSDELL
金额：
$ 21.74万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241938
关键词：
Address Anterior Architecture Attention Behavior Bilateral Breast Breast Cancer Model Breast Cancer Risk Assessment Tool Breast Cancer Risk Factor CFC1 gene Cancer Patient Cell physiology Cessation of life Development Diagnosis Disease Ductal Ductal Epithelial Cell Embryo Embryonic Development Epithelial Estrogens Exposure to Family member Future Gene Expression Genes Genetic Handedness Heart Hormonal Investigation Lead Left Link Maintenance Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mammary gland Measurement Measures Menarche Mesoderm Modeling Molecular Molecular Profiling Morphogenesis Mouse Mammary Tumor Virus Mus Neoplasms Nodal Oncogenic Organ Outcome Ovarian Pathway interactions Patients Pattern Pharmaceutical Preparations Predisposition Prevalence Primary Neoplasm Probability Process Puberty Recording of previous events Recurrence Risk Factors Role Side Signal Pathway Signal Transduction Stem cells Survival Rate Testing Time Tissues Transcription factor genes Transgenic Mice Visceral Woman base cancer risk cancer stem cell cancer type carcinogenesis cell growth fascinate improved malignant breast neoplasm mammary gland development mouse model neoplastic prognostic public health relevance rapid growth response stem tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common type of cancer that occurs in women and is second only to lung cancer as the leading cause of women's cancer-related deaths. The proposed project will address a virtually unstudied feature of the disease: the left-side prevalence of breast tumors. The overall hypothesis is that the left and right mammary glands are differentially susceptible to tumor-initiation and/or progression. If correct, differential left-right (L-R) susceptibility may be particularly important during puberty, when the rapid growth and remodeling of the embryonically established, rudimentary ductal network renders the mammary glands highly vulnerable to genetic, hormonal, and other environmental perturbations that promote neoplasias. To test this hypothesis, three mouse models of neoplastic development will be used: estrogen treated mice, which model early menarche, a well documented primary risk factor for breast cancer; MMTV-cNeu transgenic mice, a classic and widely used model of breast carcinogenesis; and MMTV-Wnt1 transgenic mice, a premier model for breast cancer stem cell studies. Putative L-R differences in mammary gland development will be systematically investigated at the morphological, cellular, and molecular levels, ranging from whole mount morphometric measurements of ductal network formation through differential L-R gene expression profiles. Particular attention will be given to the nodal signaling pathway. Nodal is a TGF? family member that is a master regulator of embryonic L-R asymmetric patterning. De-regulated expression of nodal pathway components is associated with poor prognostic outcome in breast cancer patients, suggesting an additional role for this pathway in mammary gland carcinogenesis. Specific Aim 1 will determine whether expression of nodal pathway components and ductal patterning differ in the left versus right mammary glands of mice induced to undergo early menarche via estrogen exposure. Time -course studies encompassing pubescent development will quantify gene expression profiles and measure putative differences in the epithelial stem/progenitor cell pool, ductal epithelial cell growth, survival, and branching morphogenesis. In Specific Aim 2, parallel studies will be performed in pubescent MMTV-cNeu and MMTV-Wnt1 transgenic mice to determine whether morphological and molecular L-R differences in mammary gland development arise and/or become accentuated early in oncogenesis. Because L-R bias for tumor formation also occurs for cancers in other bilaterally paired organs, and because there is emerging evidence that the 5-year survival rates for some cancers significantly differ according to the left versus right side of tumor formation, the significance of the proposed project is that investigation of breast cancer laterality ultimately may lead to improvements in the treatment and survival of breast cancer patients. PUBLIC HEALTH RELEVANCE: The proposed project will address a poorly understood aspect of breast cancer-the question of why more tumors develop in the left breast than the right. Experimentation will focus on genes and cellular processes that function during pubescent development and that may predispose left-side prevalence for tumor formation. The long-term significance of this study is that it may yield information on normal and neoplastic mammary gland development that could be used to improve delivery of current therapies or development of new treatment regimes.

描述（由申请人提供）：乳腺癌是女性最常见的癌症类型，仅次于肺癌，是女性癌症相关死亡的主要原因。拟议的项目将解决一个几乎未研究的疾病特征：左侧乳腺肿瘤的患病率。总体假设是，左乳腺和右乳腺对肿瘤发生和/或进展的敏感性不同。如果正确的话，左右（L-R）易感性差异在青春期可能特别重要，此时胚胎建立的初级导管网络的快速生长和重塑使乳腺非常容易受到遗传、激素和其他环境干扰的影响，从而促进肿瘤形成。为了检验这一假设，将使用三种肿瘤发展的小鼠模型：雌激素处理的小鼠，其模拟早期月经初潮，这是乳腺癌的一个有据可查的主要风险因素; MMTV-cNeu转基因小鼠，一种经典且广泛使用的乳腺癌发生模型;以及MMTV-Wnt 1转基因小鼠，一种用于乳腺癌干细胞研究的首要模型。将在形态、细胞和分子水平上系统研究乳腺发育中推定的L-R差异，范围从导管网络形成的整体形态测量到差异L-R基因表达谱。将特别注意节点信号通路。Nodal是TGF？家族成员，是胚胎L-R不对称模式的主要调节因子。在乳腺癌患者中，nodal通路组分的失调表达与预后不良相关，这表明该通路在乳腺癌发生中的额外作用。具体目标1将确定通过雌激素暴露诱导经历早期初潮的小鼠的左乳腺与右乳腺中淋巴结通路组分的表达和导管图案是否不同。包括青春期发育的时程研究将量化基因表达谱并测量上皮干/祖细胞库、导管上皮细胞生长、存活和分支形态发生中的推定差异。在特定目标2中，将在青春期MMTV-cNeu和MMTV-Wnt 1转基因小鼠中进行平行研究，以确定乳腺发育中的形态学和分子L-R差异是否在肿瘤发生早期出现和/或加重。由于肿瘤形成的L-R偏倚也发生在其他双侧配对器官的癌症中，并且因为有新的证据表明某些癌症的5年生存率根据肿瘤形成的左侧与右侧而显着不同，因此拟议项目的意义在于，对乳腺癌偏侧性的研究最终可能导致乳腺癌患者治疗和生存的改善。公共卫生关系：该项目将解决乳腺癌的一个鲜为人知的方面-为什么更多的肿瘤发生在左乳房比右乳房的问题。实验将集中在青春期发育过程中发挥作用的基因和细胞过程，这些基因和细胞过程可能使左侧肿瘤的形成更加容易。这项研究的长期意义在于，它可能会产生关于正常和肿瘤性乳腺发育的信息，这些信息可用于改善当前疗法的实施或开发新的治疗方案。