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性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，它们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间体。我们最近证明，Jak2和活性Stat5是必不可少的ErbB2和催乳素诱导的乳腺癌发生。此外，我们发现，Stat5增强Akt1的表达，通过转录激活这个基因从一个新的，乳腺特异性启动子。Stat5在体内的功能获得足以上调Akt1的表达和激活，随后介导乳腺上皮细胞的持续存活。因此，与PI3K/Akt1信号传导一样，活性Jak2/Stat5级联促进了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的突变和PTEN的功能丧失是在散发性以及遗传性形式的乳腺癌中观察到的常见分子畸变（例如，Cowden综合征），该项目的主要目标是检查Jak/Stat信号传导和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信号级联是一个有效的修改器的肿瘤转化的发病是由PI3K/Akt1通路的超活化与突变的PTEN肿瘤抑制基因。此外，我们预期Akt1是执行突变型PTEN和活性Stat5的致癌特性的主要下游效应子。为了通过实验解决这一假设，我们将在第一个具体目标中评估Jak2/Stat5信号传导的改变是否影响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具体目标中确定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标。由于我们已经发现乳腺特异性Akt1转录物在小鼠和人类之间是保守的，我们将在第三个具体目标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作为缺乏功能性PTEN的散发性和遗传性乳腺癌发病修饰剂的分子机制。这项研究的结果可能为扩展Jak2抑制剂作为预防乳腺癌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，特别是在乳腺上皮细胞的转录水平上调节Akt1的表达。

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.