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。我们的研究集中在Janus激酶（JAK）和信号转导和转录激活因子（STAT）。JAK和STAT是与乳腺癌有关的各种生长因子受体的“火线”中的重要中间体。我们目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，该模型通过过度刺激生长因子受体（即催乳素受体和ErbB 2）启动肿瘤发生，这些受体利用Jak 2和/或StatS和Stat 3作为信号转导子。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Jak 2的失活来抑制生长因子介导的STAT活化将减少这些肿瘤模型中肿瘤转化的发生。这将表明，靶向Jak 2是高泌乳素血症患者或有发生妊娠相关乳腺癌风险的患者预防乳腺癌的相关策略，这些患者通常是ErbB 2阳性的。相反，肿瘤细胞中Jak 2/Stat 5/3信号传导的消融（治疗性干预）可能导致不同的结果，这取决于生长因子引发的转化的类型，更重要的是，取决于进展性病变的阶段。该提案的具体目的是确定作为催乳素和ErbB 2过表达癌细胞分析的生物标志物的不同信号转导物的层次结构（目的1）。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ErbB 2之间Jak 2介导的受体串扰（目的3）。这些分析的结果可能会区分乳腺癌的亚型，其中靶向Jak 2是治疗相关的。此外，他们可能揭示泛ErbB酪氨酸激酶抑制剂和Jak 2抑制剂的组合疗法是否有益于治疗ErbB 2阳性乳腺癌。

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.