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 和乳腺上皮细胞的肿瘤转化。我们的研究集中在Janus激酶（JAK）和 信号转导子和转录激活子（STAT）。JAK和STAT是 与乳腺癌有关的各种生长因子受体的“火线”。一个主要目标 我们目前研究的一个目的是研究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ErbB 2）的肿瘤发生， 利用Jak 2和/或StatS和Stat 3作为信号换能器。我们开发了一个独特的模型系统， 在生长因子介导的肿瘤转化之前， 以及在疾病进展的特定阶段。我们假设抑制生长因子- 通过Jak 2失活介导的STAT活化将减少肿瘤转化的发生 in these tumor肿瘤models模型.这将表明，靶向Jak 2是预防乳腺癌的相关策略。 在患有高泌乳素血症的个体或有发生妊娠相关乳腺癌风险的患者中， ErbB 2阳性的癌症相反，肿瘤细胞中Jak 2/Stat 5/3信号传导的消除， 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- 开始的转化，更重要的是，进展性病变的阶段。具体目标是 我们的建议是确定一个不同的信号转导的层次（目标1），作为生物标志物， 催乳素和ErbB 2过表达癌细胞的分析。此外，拟议的研究将涉及 关于催乳素在乳腺癌中的自分泌作用的机制方面（aim 2）以及建议的 Jak 2介导的催乳素受体和ErbB 2之间的受体串扰（目的3）。的结果予以 分析可以区分乳腺癌的亚型，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抑制剂将有益于治疗ErbB 2阳性乳腺癌。

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.