Growth-Regulatory Signaling Networks in Breast Cancer

描述（由申请人提供）：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。我们目前的研究重点是Jak2和Stat5的生物学相关功能，它们是与乳腺肿瘤发生有关的各种生长因子受体的重要中介。我们最近证明Jak2和活性Stat5在ErbB2和催乳素诱导的乳腺癌发生中是必需的。此外，我们发现Stat5通过一个新的乳腺特异性启动子转录激活Akt1基因，从而增强了Akt1的表达。体内Stat5的功能获得足以上调Akt1的表达和激活，进而介导乳腺上皮细胞的持续存活。因此，像PI3K/Akt1信号一样，活跃的Jak2/Stat5级联促进了癌症的两个重要标志，即逃避细胞凋亡和生长信号的自给自足。由于PI3K突变和PTEN功能丧失是散发性和遗传性乳腺癌（如考登综合征）中常见的分子畸变，本项目的主要目标是研究Jak/Stat信号和PI3K/Akt1通路的关联是否在乳腺癌中起重要作用。我们的一般假设是，Jak2/Stat5信号级联是由PI3K/Akt1通路的过度激活与PTEN肿瘤抑制基因突变引起的肿瘤转化的有效修饰因子。此外，我们预计Akt1是执行突变型PTEN和活性Stat5的致癌特性的主要下游效应物。为了通过实验验证这一假设，我们将在第一个特定目标中评估Jak2/Stat5信号的改变是否会影响pten相关乳腺癌的发病。Akt1作用于Stat5和PTEN的下游，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Stat5诱导和PTEN相关乳腺癌的合适靶点。由于我们已经发现乳腺特异性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靶向这些独特mrna是否对乳腺癌细胞的生长和存活有影响。总的来说，这个项目的结果将深入了解Jak2和Stat5作为散发性和遗传性乳腺癌发病调节剂的分子机制，这些乳腺癌缺乏功能性PTEN。这项研究的结果可能为扩大Jak2抑制剂作为乳腺癌预防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.