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ErbB receptor signaling via small G-proteins in breast cancer

乳腺癌中通过小 G 蛋白进行的 ErbB 受体信号传导

基本信息

批准号：
8607903
负责人：
MARCELO G. KAZANIETZ
金额：
$ 36.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607903
关键词：
Actins Address Affect Anchorage-Independent Growth Animal Model Biological Assay Breast Cancer Cell Breast Cancer Model Breast Carcinoma CXCR4 gene Cancer cell line Cell model Cell physiology Cells Cytoskeleton Disease Disease Progression Dissociation Down-Regulation ERBB2 gene Epidermal Growth Factor Epidermal Growth Factor Receptor ErbB4 gene Estrogen Antagonists Etiology Family Fluorescence Resonance Energy Transfer G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTPase-Activating Proteins Gene Amplification Gene Mutation Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Heregulin Human Isoenzymes Lead Ligands Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Membrane Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutate Neoplasm Metastasis Normal Cell Nude Mice PTEN gene Pathway interactions Pertussis Toxin Phosphatidylinositols Play Properdin Property Protein Tyrosine Kinase Proteins RNA Interference Receptor Protein-Tyrosine Kinases Receptor Signaling Relative (related person)Resistance Role Signal Transduction Stimulation of Cell Proliferation Testing Therapeutic Tissue Banking Tissue Banks Toxin Transactivation Tumorigenicity Up-Regulation base cell motility chemokine inhibitor/antagonist malignant breast neoplasm member migration mouse model neutrophil novel outcome forecast overexpression prevent prognostic public health relevance receptor receptor coupling response rho rho GTPase-activating protein tripolyphosphate tumor tumor progression tumorigenesis tumorigenic wortmannin

项目摘要

DESCRIPTION (provided by applicant): The human epidermal growth factor (EGF) family of tyrosine kinase receptors consists of ErbB1 (EGFR), ErbB2 (Neu), ErbB3, and ErbB4, and plays key roles in cancer progression. Dysregulation of ErbB signaling due to hyperactivation of receptors (such as mutated EGFR or ErbB2 overexpression), overexpression of ligands (such as TGF-? or heregulins), or augmented downstream signaling (such as enhanced PI3K signaling) plays a major role in the etiology of breast cancer. We found that ligand stimulation of ErbB1 and ErbB3 receptors leads to a strong activation of the small GTPase Rac1 to promote mitogenesis and motility. The search for Rac-GEFs that mediate Rac1 activation by ErbB ligands in breast cancer cells revealed a prominent role for phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchanger-1 (P-Rex1), a Rac-GEF originally identified in neutrophils but not studied in any cancer so far. Strikingly, P-Rex1 is highly expressed in most breast cancer cell lines as well as in tumors. P-Rex1 is a PI3K- and G??-dependent Rac-GEF, and coincidentally, ErbB receptor-mediated activation of Rac1 is inhibited by Pertusis toxin, which prevents G23 subunit release from heterotrimeric Gi proteins, by the PI3K inhibitor wortmannin, and by inhibition/depletion of PI3K?, a class Ib PI3K that is activated by G?? subunits. Moreover, ErbB3-induced activation of Rac1 is dependent on the transactivation of CXCR4, a Gi-coupled receptor widely implicated in breast cancer progression, and Rac1 activation by direct stimulation of CXCR4 with the chemokine SDF-11 also depends on P-Rex1. Therefore, P-Rex1 is a common mediator of Rac activation by ErbB receptors and GPCRs in breast cancer cells. In Specific Aim 1 we will investigate whether ligand stimulation of ErbB receptors can promote the activation of P-Rex1 in breast cancer cells, and assess the functional consequences for such activation, including actin cytoskeleton reorganization, migration, and proliferation. Translocation studies as well as FRET approaches will be used to address the relative contribution of discrete PI3K isozymes and the CXCR4-G?? pathway to P-Rex1 and Rac1 activation. In Specific Aim 2 we will determine whether RNAi depletion of P-Rex1 affects tumorigenicity and metastatic dissemination of breast cancer cells driven by overexpression of an ErbB3 ligand. We will also assess the involvement of P-Rex1 in anti-estrogen resistance. In Specific Aim 3 we will determine if Rac signaling via P-Rex1 contributes to ErbB2-driven tumorigenesis and metastasis, and whether this is mediated by the CXCR4-G??-PI3K? pathway. We will generate mammary-specific mouse models for P-Rex1 overexpression and determine whether it can lead to tumor formation or cooperate with ErbB2 overexpression. In Specific Aim 4 the goal is to determine whether P-Rex1 is a hallmark of human breast cancer, and P-Rex1 expression in human tumors correlates with signaling parameters. The identification of P-Rex1 as an effector of ErbB receptors may have major relevance for understanding the molecular basis and etiology of breast cancer as well as significant prognostic and therapeutic implications.

描述（由申请人提供）：酪氨酸激酶受体的人表皮生长因子（EGF）家族由ErbB1（EGFR）、ErbB2（Neu）、ErbB3和ErbB4组成，在癌症进展中发挥关键作用。由于受体过度激活（例如突变的 EGFR 或 ErbB2 过表达）、配体过表达（例如 TGF-β 或调蛋白）或增强的下游信号传导（例如增强的 PI3K 信号传导）导致的 ErbB 信号传导失调在乳腺癌病因学中发挥着重要作用。我们发现配体刺激 ErbB1 和 ErbB3 受体会导致小 GTPase Rac1 的强烈激活，从而促进有丝分裂和运动。在乳腺癌细胞中寻找通过 ErbB 配体介导 Rac1 激活的 Rac-GEF，揭示了磷脂酰肌醇-3,4,5-三磷酸依赖性 Rac 交换器-1 (P-Rex1) 的显着作用，这是一种最初在中性粒细胞中发现的 Rac-GEF，但迄今为止尚未在任何癌症中进行研究。引人注目的是，P-Rex1 在大多数乳腺癌细胞系以及肿瘤中高度表达。 P-Rex1 是一种 PI3K 和 G?? 依赖性 Rac-GEF，巧合的是，ErbB 受体介导的 Rac1 激活受到百日咳毒素的抑制，百日咳毒素可防止异三聚体 Gi 蛋白释放 G23 亚基、PI3K 抑制剂渥曼青霉素以及 PI3K?（Ib 类 PI3K）的抑制/耗尽是G激活的？？亚单位。此外，ErbB3诱导的Rac1激活依赖于CXCR4的反式激活，CXCR4是一种广泛参与乳腺癌进展的Gi偶联受体，并且趋化因子SDF-11直接刺激CXCR4而激活Rac1也依赖于P-Rex1。因此，P-Rex1 是乳腺癌细胞中 ErbB 受体和 GPCR 激活 Rac 的常见介质。在具体目标 1 中，我们将研究 ErbB 受体的配体刺激是否可以促进乳腺癌细胞中 P-Rex1 的激活，并评估这种激活的功能后果，包括肌动蛋白细胞骨架重组、迁移和增殖。易位研究以及 FRET 方法将用于解决离散 PI3K 同工酶和 CXCR4-G?? 的相对贡献？ P-Rex1 和 Rac1 激活途径。在具体目标 2 中，我们将确定 P-Rex1 的 RNAi 消耗是否会影响由 ErbB3 配体过度表达驱动的乳腺癌细胞的致瘤性和转移性扩散。我们还将评估 P-Rex1 在抗雌激素抵抗中的作用。在具体目标 3 中，我们将确定通过 P-Rex1 的 Rac 信号传导是否有助于 ErbB2 驱动的肿瘤发生和转移，以及这是否由 CXCR4-G??-PI3K 介导？途径。我们将建立 P-Rex1 过表达的乳腺特异性小鼠模型，并确定它是否会导致肿瘤形成或与 ErbB2 过表达相配合。具体目标 4 的目标是确定 P-Rex1 是否是人类乳腺癌的标志，以及人类肿瘤中 P-Rex1 的表达与信号转导参数相关。 P-Rex1 作为 ErbB 受体效应子的鉴定可能对于了解乳腺癌的分子基础和病因学以及重要的预后和治疗意义具有重要意义。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of a P-Rex1 gene signature in breast cancer cells.

DOI：
10.18632/oncotarget.10285
发表时间：
2016-08-09
期刊：
Oncotarget
影响因子：
0
作者：
Barrio-Real L;Wertheimer E;Garg R;Abba MC;Kazanietz MG
通讯作者：
Kazanietz MG

Rac1 takes center stage in pancreatic cancer and ulcerative colitis: quantity matters.

DOI：
10.1053/j.gastro.2011.06.027
发表时间：
2011-08
期刊：
Gastroenterology
影响因子：
29.4
作者：
E. Wertheimer;M. Kazanietz
通讯作者：
E. Wertheimer;M. Kazanietz

P-Rex1 is dispensable for Erk activation and mitogenesis in breast cancer.

DOI：
10.18632/oncotarget.25584
发表时间：
2018-06-19
期刊：
Oncotarget
影响因子：
0
作者：
Barrio-Real L;Lopez-Haber C;Casado-Medrano V;Goglia AG;Toettcher JE;Caloca MJ;Kazanietz MG
通讯作者：
Kazanietz MG

Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation.