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（由适用提供）：乳腺癌是女性癌症死亡的第二大原因。在美国，近12％的妇女将在其一生中发展乳腺癌，每年约有40,000人死于该疾病。乳腺癌的分子和细胞起源是高度异质性的。基因分析显示至少五个不同的亚型。一种这样的亚型是“ HER2”，约占所有被诊断乳腺癌的30％。 HER2乳腺癌是由于表皮生长因子受体（EGFR）家族蛋白HER2/EGFR2的过表达或扩增而发展的。因此，对乳房中的EGFR信号的了解更加重要。 EGFR信号已显示在调节乳腺发育中起关键作用。有证据表明，表明EGFR中的突变导致发育缺陷。此外，多能祖细胞中的EGFR信号增强了特定的分支效应和细胞脂肪决策。这些发育观察结果也与乳腺癌相关，因为人们认为异质性主要来自不同的乳腺上皮细胞（MEC），这些细胞（MEC）用作原始细胞。 RAS途径像EGFR这样的受体酪氨酸激酶的下游激活。 RAS信号部分通过RAS激活蛋白质来控制，包括Ras鸟苷核苷酸释放蛋白1（RASGRP1）。来自我们实验室的工作表明，RASSGRP1调节的RAS信号强度通常可以控制增殖和分化的平衡。淋巴细胞中异常的RASGRP1表达会导致发育延迟，并导致白血病的发作和进展。此外，我们最近发现RASGRP1矛盾地起作用，以限制肠上皮细胞内的EGFR-RAS信号，从而在RasgRP1功能受到扰动时导致增殖增强和肠道祖细胞分化的变化。特定的EGFR-RASGEF-RAS信号如何影响MEC谱系的发展，癌症的启动和进展以及此处RASGRP1的特定作用仍然未知。鉴于在正常和恶性乳房生长过程中已知的滴定EGFR-RAS信号的重要性，我假设RASGRP1通过控制这些细胞中EGFR-RAS信号的强度，在乳腺上皮祖细胞生长和分化中起重要但出乎意料的作用。为了检验我们的假设，我们的实验室已经生成了带有消融（Rasgrp1 - / - ）和受损（Rasgrp1anaef）Rasgrp1的鼠标模型。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。我将表征RASGRP1在MEC中的表达（AIM 1），并确定不同的EGFR-RASGRP1信号如何影响开发过程中MEC谱系（AIM 2）。最后，我将研究EGFR-RASGRP1信号在乳腺癌中的作用（AIM 3）。我们预计，我们的研究将为RASGRP1在发育和癌症过程中MECS谱系中EGFR-RAS信号的特征提供重大见解。