Growth-Regulatory Signaling Networks in Breast Cancer

描述(申请人提供)：我们的长期目标是阐明生长调节信号网络如何控制正常和肿瘤乳腺上皮细胞的增殖、分化和存活。我们目前的研究集中在JAK2和Stat5的生物学相关功能上，这两个基因是多种生长因子受体的重要中介，参与了乳腺肿瘤的发生。我们最近证明JAK2和激活的Stat5在ErbB2和催乳素诱导的乳腺癌的发生中是必不可少的。此外，我们发现，Stat5通过转录激活Akt1基因来增强Akt1的表达，该基因来自一种新的乳腺特异启动子。Stat5在体内的功能增强足以上调Akt1的表达和激活，从而介导乳腺上皮细胞的持续生存。因此，像PI3K/Akt1信号一样，活跃的JAK2/Stat5级联信号通路促进了癌症的两个重要特征，即逃避凋亡和生长信号的自给自足。由于PI3K突变和PTEN功能丧失是在散发性和遗传性乳腺癌(如Cowden综合征)中常见的分子异常，本项目的主要目标是研究Jak/Stat信号和PI3K/Akt1通路是否在乳腺癌中发挥重要作用。我们的一般假设是，JAK2/Stat5信号级联是肿瘤转化开始的有效修饰物，肿瘤转化是由PI3K/Akt1途径的过度激活和PTEN抑癌基因的突变引起的。此外，我们预计Akt1是一个主要的下游效应因子，执行突变的PTEN和活性Stat5的致癌特性。为了在实验上解决这一假设，我们将在第一个特定目标中评估JAK2/Stat5信号的变化是否影响PTEN相关乳腺癌的发生。AKT1在Stat5和PTEN下游发挥作用，因此我们将在第二个特定目标中确定Akt1是否是预防和治疗Stat5诱导的和PTEN相关的乳腺癌的合适靶点。由于我们已经发现乳腺特异的Akt1转录本在小鼠和人类之间是保守的，我们将在第三个特定目标中评估针对这些独特的mRNAs是否对乳腺癌细胞的生长和存活有影响。总而言之，该项目的结果将深入了解JAK2和STAT5作为缺乏功能PTEN的散发性和遗传性乳腺癌发病的修饰物的分子机制。这项研究的结果可能为扩大JAK2抑制剂作为乳腺癌预防的新方法的使用提供证据，该项目将确定Akt1是否是PTEN相关乳腺癌的治疗靶点。最后，我们将评估一种新的策略来调节Akt1在转录水平上的表达，特别是在乳腺上皮中。

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.