Growth-Regulatory Signaling Networks in Breast Cancer

乳腺癌的生长调节信号网络

基本信息

批准号：
9029286
负责人：
Kay-Uwe Wagner
金额：
$ 25.59万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-04 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029286
关键词：
1-Phosphatidylinositol 3-Kinase AKT1 gene Ablation Address Affect Apoptosis Apoptotic Biological Breast Cancer Cell Breast Cancer Prevention Breast Epithelial Cells Cancer Cell Growth Cancer Model Cell Survival Cyclin D1 Down-Regulation Etiology Event Female Fire - disasters Genes Germ-Line Mutation Goals Growth Growth Factor Receptors Human Inherited Janus kinase Knock-out Ligands Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mediator of activation protein Messenger RNA Modeling Molecular Molecular Abnormality Multiple Hamartoma Syndrome Mus Mutation Neoplasms Neoplastic Cell Transformation Nuclear Oncogenic Organ Outcome Study PTEN gene Pathway interactions Patients Phosphotransferases Play Prevention Prolactin Property Receptor Signaling Role STAT protein Signal Transduction Tissues Transcript Transcriptional Activation Tumor Suppressor Proteins UXT gene Woman breast tumorigenesis gain of function in vivo inhibitor/antagonist insight interest loss of function malignant breast neoplasm mammary epithelium mouse model mutant neoplastic novel novel strategies prevent promoter research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to elucidate how growth-regulatory signaling networks control the multiplication, differentiation, and survival of normal and neoplastic mammary epithelial cells. Our current studies focus on the biologically relevant functions of Jak2 and Stat5 which are important intermediaries in the lines of fire of various growth factor receptors that are implicated in breast tumorigenesis. We recently demonstrated that Jak2 and active Stat5 are essential for ErbB2- and prolactin-induced mammary carcinogenesis. In addition, we discovered that Stat5 enhances the expression of Akt1 through transcriptional activation of this gene from a novel, mammary-specific promoter. A gain-of-function of Stat5 in vivo is sufficient to upregulate the expression and activation of Akt1, which subsequently mediates a sustained survival of mammary epithelial cells. Hence, like PI3K/Akt1 signaling, an active Jak2/Stat5 cascade facilitates two important hallmarks of cancer, i.e. evasion from apoptosis and self-sufficiency in growth signals. Since mutations in PI3K and loss-of-function of PTEN are common molecular aberrations observed in sporadic as well as hereditary forms of breast cancer (e.g., Cowden Syndrome), the primary goal of this project is to examine whether the association of Jak/Stat signaling and the PI3K/Akt1 pathway plays an important role in breast cancer. Our general hypothesis is that the Jak2/Stat5 signaling cascade is a potent modifier for the onset of neoplastic transformation that is caused by a hyperactivation of the PI3K/Akt1 pathway in conjunction with a mutation in the PTEN tumor suppressor. In addition, we anticipate that Akt1 is a main downstream effector that executes oncogenic properties of mutant PTEN and active Stat5. To experimentally address this hypothesis, we will assess in the first specific aim whether alterations in Jak2/Stat5 signaling affect the onset of PTEN-associated mammary cancer. Akt1 acts downstream of Stat5 and PTEN, and we will therefore determine in the second specific aim whether Akt1 is a suitable target for the prevention and treatment of Stat5-induced and PTEN-associated mammary cancer. Since we have found that the mammary-specific Akt1 transcripts are conserved between mice and humans, we will assess in the third specific aim whether targeting these unique mRNAs has an effect on breast cancer cell growth and survival. Collectively, the results of this project will give insight into the molecular mechanisms by which Jak2 and Stat5 act as modifiers for the onset of sporadic as well as hereditary forms of breast cancer that lack functional PTEN. The outcome of this study might provide evidence for extending the use of Jak2 inhibitors as a novel approach toward breast cancer prevention, and this project will establish whether Akt1 is a therapeutic target for PTEN-associated breast cancers. Finally, we will assess a new strategy to modulate the expression of Akt1 on the transcriptional level specifically in the mammary epithelium.

描述（由申请人提供）：我们的长期目标是阐明生长调节性信号网络如何控制正常和肿瘤乳腺上皮细胞的乘法，分化和存活。我们目前的研究着重于JAK2和STAT5的生物学相关功能，这些功能是与乳腺肿瘤发生有关的各种生长因子受体的火线中的重要中介。我们最近证明，JAK2和Active STAT5对于ERBB2和催乳素诱导的乳腺癌发生至关重要。此外，我们发现STAT5通过来自新型乳腺特异性启动子的转录激活来增强Akt1的表达。 STAT5在体内的功能获得的功能足以上调Akt1的表达和激活，随后介导了乳腺上皮细胞的持续存活。因此，与PI3K/AKT1信号一样，主动JAK2/STAT5级联级联有助于癌症的两个重要标志，即逃避凋亡和生长信号的自给自足。由于PI3K中的突变和PTEN的功能丧失是在零星和遗传形式的乳腺癌（例如Cowden综合征）中观察到的常见分子畸变，因此该项目的主要目标是检查JAK/STAT信号的关联以及PI3K/AKT1途径在乳腺癌中是否起重要作用。我们的一般假设是，JAK2/STAT5信号传导级联反应是肿瘤转化发作的有效修饰符，这是由PI3K/AKT1途径与PTEN抑制剂突变结合的过度激活引起的。此外，我们预计AKT1是一个主要的下游效应子，它可以执行突变体PTEN和Active STAT5的致癌特性。为了实验解决这一假设，我们将在第一个特定的目的中评估JAK2/STAT5信号传导中的改变是否影响PTEN相关乳腺癌的开始。 AKT1在STAT5和PTEN的下游作用，因此我们将在第二个特定目的中确定AKT1是否是预防和治疗与STAT5诱导的和PTEN相关的乳腺癌的合适靶标。由于我们发现乳腺特异性的AKT1转录本是小鼠和人之间保守的，因此我们将在第三个特定目的中评估靶向这些独特的mRNA是否对乳腺癌细胞的生长和存活有影响。总的来说，该项目的结果将深入了解JAK2和STAT5作为零星和遗传形式的乳腺癌的修饰符，而乳腺癌缺乏功能性PTEN。这项研究的结果可能提供了扩展使用JAK2抑制剂作为预防乳腺癌的新方法的证据，该项目将确定AKT1是否是PTEN相关乳腺癌的治疗靶标。最后，我们将评估一种新策略，以调节Akt1在乳腺上皮中的转录水平上的表达。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

AKT3 drives adenoid cystic carcinoma development in salivary glands.

DOI：
10.1002/cam4.1293
发表时间：
2018-03
期刊：
Cancer medicine
影响因子：
4
作者：
Zboray K;Mohrherr J;Stiedl P;Pranz K;Wandruszka L;Grabner B;Eferl R;Moriggl R;Stoiber D;Sakamoto K;Wagner KU;Popper H;Casanova E;Moll HP
通讯作者：
Moll HP

Putting the brakes on mammary tumorigenesis: loss of STAT1 predisposes to intraepithelial neoplasias.

抑制乳腺肿瘤的发生：STAT1 的缺失易导致上皮内瘤变。

DOI：
10.18632/oncotarget.371
发表时间：
2011
期刊：
Oncotarget
影响因子：
0
作者：
Schneckenleithner,Christine;Bago-Horvath,Zsuzsanna;Dolznig,Helmut;Neugebauer,Nina;Kollmann,Karoline;Kolbe,Thomas;Decker,Thomas;Kerjaschki,Dontscho;Wagner,Kay-Uwe;Müller,Mathias;Stoiber,Dagmar;Sexl,Veronika
通讯作者：
Sexl,Veronika

Erythropoietin protects against diabetes through direct effects on pancreatic beta cells.

DOI：
10.1084/jem.20100665
发表时间：
2010-12-20
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Choi D;Schroer SA;Lu SY;Wang L;Wu X;Liu Y;Zhang Y;Gaisano HY;Wagner KU;Wu H;Retnakaran R;Woo M
通讯作者：
Woo M

Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein bax.

通过促凋亡蛋白bax的过度表达，强制功能分化的乳腺退化。

DOI：
10.1002/dvg.20691
发表时间：
2011
期刊：
Genesis (New York, N.Y. : 2000)
影响因子：
0
作者：
Rucker3rd,EdmundB;Hale,AmberN;Durtschi,DavidC;Sakamoto,Kazuhito;Wagner,Kay-Uwe
通讯作者：
Wagner,Kay-Uwe

Targeting janus kinase 2 in Her2/neu-expressing mammary cancer: Implications for cancer prevention and therapy.