Crosstalk TGFbeta and HER2 (ErbB2) Signaling in Mammary Tumorigenesis

描述（由申请方提供）：受体酪氨酸激酶HER 2（ErbB 2）的过表达和转化生长因子的激活？？(TGF?)信号传导都与乳腺癌向更具转移性表型的进展相关。HER 2原癌基因的过表达允许TGF？的促肿瘤作用。这个建议的目的是研究TGF？和HER 2，其不仅涉及细胞内/细胞间事件，而且涉及微环境事件。我们假设，在HER 2介导的转化，TGF？可以1）动态调节HER 2亚细胞分布和HER 2细胞底物/信号转导物的库; 2）通过调节HER 2磷酸化和细胞运输来调节HER 2信号传导的大小和幅度; 3）修饰ECM和基质以产生促进肿瘤生长和转移的微环境;和4）减弱HER 2依赖性细胞对HER 2治疗性抑制剂的反应。了解时间和空间特性之间的串扰TGF？和HER 2信号传导的研究将揭示新的治疗靶点，并可能优化目前的HER 2治疗抑制剂。结果也将阐明对TGF？和HER 2基因。将努力实现以下具体目标。具体目标1：确定是否激活TGF？受体在空间和时间上调节乳腺上皮细胞的HER 2信号传导，以及TGF？- 诱导的细胞骨架重塑影响HER 2分布、运输和信号传导。具体目标2：为了确定Rac/Pak通路是否是由HER 2和TGF β之间的相互作用介导的侵袭性和存活所必需的，HER 2是否是Pak 1的底物，以及HER 2是否与Pak 1和活性Rac 1在原发性乳腺肿瘤中共定位。具体目标3：确定是否TGF？和HER 2通过利用蛋白质组学方法改变微环境成分，以及这些是否有助于小鼠的肿瘤发生。具体目标4：确定是否激活TGF？信号可以赋予耐药性的治疗抑制剂的HER 2乳腺癌细胞和PI 3 K和Rac/Pak途径的作用，在TGF？- 赋予抵抗

DESCRIPTION (provided by applicant): Overexpression of the receptor tyrosine kinase HER2 (ErbB2) and activation of transforming growth factor ??(TGF?) signaling are both associated with progression of breast cancers to a more metastatic phenotype. Overexpression of the HER2 proto-oncogene is permissive for the tumor promoting effects of TGF?. The objective of this proposal is to study the reciprocal, temporal and spatial crosstalk between TGF? and HER2, which involves not only intra-/intercellular but also microenvironmental events. We hypothesize that in HER2-mediated transformation, TGF? can 1) dynamically modulate HER2 subcellular distribution and the repertoire of HER2 cellular substrates/signal transducers; 2) regulate the magnitude and amplitude of HER2 signaling through the modulation of HER2 phosphorylation and cellular trafficking; 3) modify the ECM and stroma to create a microenvironment that facilitates tumor growth and metastasis; and 4) attenuate the response of HER2-dependent cells to therapeutic inhibitors of HER2. Understanding the temporal and spatial features of the crosstalk between TGF? and HER2 signaling will disclose new therapeutic targets, as well as potentially allow the optimization of current therapeutic inhibitors of HER2. The results will also shed light on the perspective of a combined therapy against TGF? and HER2 in breast cancer patients. The following specific aims will be pursued. Specific aim 1: to determine whether activated TGF? receptors spatially and temporally modulate HER2 signaling in mammary epithelial cells and how TGF? -induced cytoskeleton remodeling affects HER2 distribution, trafficking and signaling. Specific aim 2: to determine whether the Rac/Pak pathway is required for the invasiveness and survival mediated by the interaction between HER2 and TGF?, whether HER2 is a substrate of Pak1 and whether HER2 colocalizes with Pak1 and active Rac1 in primary breast tumors. Specific aim 3: to determine whether TGF? and HER2 modify microenvironmental components by utilizing proteomic approaches and whether these contribute to tumorigenesis in mice. Specific aim 4: to determine whether activated TGF? signaling can confer resistance to therapeutic inhibitors of HER2 in mammary cancer cells and the role of PI3K and Rac/Pak pathways in TGF? -conferred resistance.