Growth-Regulatory Signaling Networks in Breast Cancer

我们的长期目标是阐明生长调节信号网络如何调节正常生长。 乳腺上皮细胞的肿瘤性转化。我们的研究重点是Janus激酶(JAK)和 信号转导和转录激活因子(STATs)。JAKS和STATS是 与乳腺癌有关的各种生长因子受体的“火线”。首要目标 我们目前的研究之一是检查JAK/STAT信号在乳腺癌模型中是如何改变的 通过过度刺激生长因子受体(即催乳素受体和ErbB2)而发生肿瘤 使用JAK2和/或STATS和STAT3作为信号传感器。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对JAK/STAT信号进行基因修饰 在疾病进展的特定阶段。我们假设抑制生长因子- 通过失活JAK2介导的STATS激活将减少肿瘤转化的开始 在这些肿瘤模型中。这将表明，靶向JAK2是预防乳腺癌的相关策略 高催乳素血症患者或有患妊娠相关乳房风险的患者 经常是ErbB2阳性的癌症。相反，JAK2/Stat5/3信号在肿瘤中的消融 细胞(治疗干预)可能会导致不同的结果，这取决于生长因子的类型- 启动转化，更重要的是，病变进展的阶段。这样做的具体目的是 提案是确定不同信号转导的层次结构(目标1)，作为生物标记物 催乳素和ErbB2过表达癌细胞的分析。此外，拟议的研究将涉及 催乳素在乳腺癌中自分泌作用的机制(AIM2)及其建议 JAK2介导的催乳素受体和ErbB2之间的受体串扰(目标3)。这些研究的结果 分析可能区分乳腺癌的亚型，在这些亚型中，靶向JAK2具有治疗意义。 此外，它们可能揭示PAN-ErbB酪氨酸激酶抑制剂和 JAK2抑制剂将有益于ErbB2阳性乳腺癌的治疗。

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 (aim2) 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.