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调节乳腺上皮细胞的正常生长和肿瘤转化。我们的研究重点是Janus激酶（JAKs）和信号转导和转录激活因子（STATs）。jak和STATs是与乳腺癌有关的各种生长因子受体“火线”的重要中介。我们当前研究的主要目的是研究JAK/STAT信号如何在乳腺癌模型中改变，这些模型通过过度刺激利用Jak2和/或StatS和Stat3作为信号转导的生长因子受体（即催乳素受体和ErbB2）来启动肿瘤发生。我们开发了一种独特的模型系统，使我们能够在生长因子介导的肿瘤转化之前和疾病进展的特定阶段对JAK/STAT信号进行遗传修饰。我们假设，通过Jak2的失活抑制生长因子介导的STATs激活将减少这些肿瘤模型中肿瘤转化的发生。这表明靶向Jak2是一种预防乳腺癌的相关策略，适用于患有高泌乳素血症的个体或经常出现erbb2阳性的妊娠相关乳腺癌的患者。相反，肿瘤细胞中Jak2/Stat5/3信号的消融（治疗干预）可能会导致不同的结果，这取决于生长因子启动转化的类型，更重要的是，取决于病变进展的阶段。本提案的具体目的是确定不同信号转导的层次结构（目的1），作为分析催乳素和ErbB2过表达癌细胞的生物标志物。此外，拟议的研究将解决催乳素在乳腺癌中自分泌作用的机制方面（目的2），以及催乳素受体和ErbB2之间jak2介导的受体串扰（目的3）。这些分析的结果可能区分乳腺癌亚型，其中靶向Jak2是治疗相关的。此外，它们可能揭示泛erbb酪氨酸激酶抑制剂和Jak2抑制剂的联合治疗是否有益于erbb2阳性乳腺癌的治疗。

DESCRIPTION (provided by applicant): Our long-term objective is to elucidate how growth-regulatory signaling networks regulate normal growth and neoplastic transformation of mammary epithelial cells. Our studies focus on Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). JAKs and STATs are important intermediaries in "the lines of fire" of various growth factor receptors that are implicated in breast cancer. A primary objective of our current research is to examine how JAK/STAT signaling is altered in breast cancer models that initiate tumorigenesis through hyperstimulation of growth factor receptors (i.e. prolactin receptor and ErbB2) that utilize Jak2 and/or StatS and Stat3 as signal transducers. We developed a unique model system that enables us to genetically modify JAK/STAT signaling both prior to growth factor-mediated neoplastic transformation and during particular stages of the progressing disease. We hypothesize that inhibiting the growth factor- mediated activation of STATs through inactivation of Jak2 will reduce the onset of neoplastic transformation in these tumor models. This will suggest that targeting Jak2 is a relevant strategy for breast cancer prevention in individuals with hyperprolactinemia or patients that are at risk of developing pregnancy-associated breast cancers that are frequently ErbB2-positive. In contrast, the ablation of Jak2/Stat5/3 signaling in neoplastic cells (therapeutic intervention) might result in a different outcome depending on the type of growth factor- initiated transformation, and, more importantly, the stage of the progressing lesion. The specific aims of this proposal are to determine a hierarchy of diverse signaling transducers (aim 1) that serve as biomarkers for the analysis of prolactin and ErbB2 overexpressing cancer cells. Furthermore, the proposed studies will address mechanistic aspects about the autocrine role of prolactin in breast cancer (aim 2) as well as the suggested Jak2-mediated receptor crosstalk between the prolactin receptor and ErbB2 (aim 3). The results of these analyses might, discriminate subtypes of breast cancer, in which targeting Jak2 is therapeutically relevant. Furthermore, they might reveal whether a combinatorial therapy of pan-ErbB tyrosine kinase inhibitors and Jak2 inhibitors would be beneficial for the treatment of ErbB2-positive breast cancers.