RAsGRP1 signals in breast development and cancer

RAsGRP1 在乳腺癌发育和癌症中的信号

基本信息

批准号：
9124315
负责人：
Alexandr Samocha
金额：
$ 3.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124315
关键词：
Ablation Accounting Address Affect Alleles Biochemical Biological Biological Assay Breast Breast Cancer Patient Breast Carcinoma Breast Epithelial Cells Cancer Etiology Cell Differentiation process Cell Fate Control Cell Line Cell Lineage Cell Maturation Cells Cessation of life Colorectal Data Data Set Defect Development Developmental Delay Disorders Disease Disease Progression Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Epithelial Cells Equilibrium FRAP1 gene Family Fatty acid glycerol esters Genes Genotype Goals Growth Growth Factor Receptors Heterogeneity Human Hyperplasia Immunohistochemistry In Vitro Intestines Lead Life Link Lymphocyte Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary gland Measures Mediating Metabolism Mission Molecular Multipotent Stem Cells Mus Mutate Mutation Myeloid Leukemia Nucleotides Organoids Outcome Pathway interactions Patients Pattern Play Population Positioning Attribute Protein Family Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation of Cell Size Research Personnel Role Sampling Sampling Studies Shapes Signal Pathway Signal Transduction Son Sorting - Cell Movement Staining method Stains Stem cells Structure T-Cell Receptor T-Lymphocyte Testing The Cancer Genome Atlas Thymus Gland Time Tissues United States National Institutes of Health Woman Work breast cancer diagnosis cancer initiation cell growth in vivo insight interest leukemia malignant breast neoplasm mammary gland development mouse model overexpression progenitor public health relevance ras Guanine Nucleotide Exchange Factors receptor tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women. Nearly 12% of women in the U.S. will develop breast cancer over the course of their life and about 40,000 will die each year from the disease. The molecular and cellular origins of breast cancer are highly heterogeneous. Gene profiling has revealed at least five distinct subtypes. One such subtype is "Her2", which account for approximately 30% of all diagnosed breast cancers. Her2 breast cancers develop as a result of the overexpression or amplification of the epidermal growth factor receptor (EGFR) family protein Her2/EGFR2. Therefore, gaining better insight into EGFR signaling in the breast is critically important. EGFR signaling has been shown to play a key role in regulating mammary gland development. Evidence has emerged that shows inactivating mutations in EGFR lead to developmental defects. Further, augmented EGFR signals in multipotent progenitor cells drive specific branching effects and cell fate decisions. These developmental observations are also of relevance to breast cancer, since it is thought that the heterogeneity predominantly derives from distinct mammary epithelial cells (MECs) serving as the cell of origin. The Ras pathway is activated downstream of receptor tyrosine kinases, like EGFR. Ras signals are controlled in part by Ras activating proteins, including Ras guanyl-nucleotide releasing protein 1 (Rasgrp1). Work from our lab has shown that Ras signal intensity, as modulated by Rasgrp1, often acts to control the balance of proliferation and differentiation. Aberrant Rasgrp1 expression in lymphocytes leads to developmental delay and contributes to onset and progression of leukemia. Further, we have recently discovered Rasgrp1 acts paradoxically to limit EGFR-Ras signals within intestinal epithelial cells, resulting in enhanced proliferation and changes to intestinal progenitor cell differentiation when Rasgrp1 function is perturbed. How specific EGFR- RasGEF-Ras signals impact development of MEC lineages, cancer initiation and progression, and the specific role of Rasgrp1 herein remains unknown. Given the known importance of titrated EGFR-Ras signals during normal and malignant breast growth, I hypothesize that Rasgrp1 plays an important but unexplored role in mammary epithelial progenitor cell growth and differentiation by controlling the intensity of EGFR-Ras signals in these cells. To test our hypotheses, our lab has generated mouse models with ablated (Rasgrp1-/-) and impaired (Rasgrp1Anaef) Rasgrp1. We have also developed biochemical-, cell biological-, and in vivo- approaches to reveal molecular insights and have acquired critical preliminary data. I will characterize the expression of Rasgrp1 in MECs (Aim 1) and determine how distinct EGFR-Rasgrp1 signals impact MEC lineages during development (Aim 2). Lastly, I will investigate the role of EGFR-Rasgrp1 signaling in breast cancer (Aim 3). We anticipate that our studies will provide significant insights into how Rasgrp1 shapes the character of EGFR-Ras signals in MECs lineages during development and cancer.

描述（由申请人提供）：乳腺癌是女性癌症死亡的第二大原因，近 12% 的美国女性在一生中会患上乳腺癌，每年约有 40,000 人死于这种疾病。乳腺癌的细胞起源具有高度异质性，基因分析揭示了至少五种不同的亚型，其中一种亚型是“Her2”，约占所有诊断乳腺癌的 30%。 Her2 乳腺癌是表皮生长因子受体 (EGFR) 家族蛋白 Her2/EGFR2 过度表达或扩增的结果，因此，更好地了解乳腺癌中的 EGFR 信号传导至关重要。已有证据表明 EGFR 失活突变会导致发育缺陷，此外，多能祖细胞中 EGFR 信号的增强会驱动特定的分支效应并导致发育缺陷。这些发育观察也与乳腺癌有关，因为人们认为异质性主要源自作为起源细胞的不同乳腺上皮细胞 (MEC)，Ras 通路在受体酪氨酸激酶的下游被激活。像 EGFR 一样，Ras 信号部分由 Ras 激活蛋白控制，包括 Ras 鸟苷酸释放蛋白 1 (Rasgrp1)。 Rasgrp1 受 Rasgrp1 调节，通常起到控制增殖和分化平衡的作用，异常的 Rasgrp1 表达会导致淋巴细胞发育迟缓，并导致白血病的发生和进展。此外，我们最近发现 Rasgrp1 的作用自相矛盾，限制了 EGFR-Ras 信号。当 Rasgrp1 功能受到干扰时，EGFR-RasGEF-Ras 的特异性会增加，从而导致肠上皮细胞增殖增强并改变肠祖细胞分化。信号影响 MEC 谱系的发育、癌症的发生和进展，并且 Rasgrp1 在本文中的具体作用仍然未知。鉴于已知滴定的 EGFR-Ras 信号在正常和恶性乳腺生长过程中的重要性，我发现 Rasgrp1 在其中发挥着重要但尚未探索的作用。为了测试我们的假设，我们的实验室制作了消融的小鼠模型。 (Rasgrp1-/-) 和受损 (Rasgrp1Anaef) Rasgrp1 我们还开发了生化、细胞生物学和体内方法来揭示分子见解，并获得了关键的初步数据，我将描述 MEC 中 Rasgrp1 的表达。目标 1) 并确定不同的 EGFR-Rasgrp1 信号在发育过程中如何影响 MEC 谱系（目标 2）。乳腺癌中的 EGFR-Rasgrp1 信号传导（目标 3）我们预计我们的研究将为 Rasgrp1 如何在发育和癌症过程中塑造 MEC 谱系中 EGFR-Ras 信号的特征提供重要见解。