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火线中的重要中介。我们最近证明，Jak2 和活性 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 通过新型乳腺特异性启动子转录激活 Akt1 基因来增强该基因的表达。体内 Stat5 的功能获得足以上调 Akt1 的表达和激活，从而介导乳腺上皮细胞的持续存活。因此，与 PI3K/Akt1 信号传导一样，活跃的 Jak2/Stat5 级联有助于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（例如考登综合征）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 信号传导和 PI3K/Akt1 通路的关联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发生的有效调节剂，肿瘤转化是由 PI3K/Akt1 通路过度激活以及 PTEN 肿瘤抑制因子突变引起的。此外，我们预计 Akt1 是执行突变 PTEN 和活性 Stat5 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会影响 PTEN 相关乳腺癌的发病。 Akt1 作用于 Stat5 和 PTEN 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 诱导和 PTEN 相关乳腺癌的合适靶点。由于我们发现乳腺特异性 Akt1 转录本在小鼠和人类之间是保守的，因此我们将在第三个具体目标中评估针对这些独特 mRNA 是否对乳腺癌细胞生长和存活有影响。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调节剂的分子机制。这项研究的结果可能为扩大 Jak2 抑制剂的使用作为预防乳腺癌的新方法提供证据，并且该项目将确定 Akt1 是否是 PTEN 相关乳腺癌的治疗靶点。最后，我们将评估一种在转录水平上特别是在乳腺上皮中调节 Akt1 表达的新策略。

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.