Identification of CREB-regulating microRNAs and the characterization of their function and clinical relevance in HER-2/neu-positive mammary carcinoma

CAMP反应元件结合蛋白(CREB)1是一种转录因子，参与调节细胞增殖、凋亡和细胞周期等多种生理过程。此外，CREB的表达和活性在不同来源的肿瘤中被检测到，这往往与肿瘤患者的疾病进展和预后不良有关。自己的初步工作证明，在HER-2/neu介导的体外转化模型中，HER-2/neu和CREB的表达之间存在相关性，在HER-2/neu+乳腺癌中，HER-2/neu+乳腺癌伴随着细胞生长增加和体内外细胞凋亡减少。尽管CREB调控的过程已经有了很好的描述，但关于CREB的转录后调控信息很少。为了明确CREB调控miRNAs是否可以调控CREB的表达，本课题的目的是：(1)鉴定CREB调控的一般miRNAs，(Ii)鉴定这些miRNAs的表达、调控和功能，(Iii)定义HER-2/neu调控的CREB调控miRNAs，(Iv)分析CREB调控miRNAs在HER-2/neu+肿瘤中的临床意义及其与化疗耐药的关系，以及(V)确定它们的调控作为HER-2/neu过表达肿瘤的新的治疗概念。这些分析不仅将扩展miRNA介导的CREB表达调控的知识，还将深入了解miRNA/CREB/HER-2/neu网络的功能作用，这可能导致开发治疗初治以及耐药HER-2/neu过表达肿瘤的创新策略。

The cAMP response element binding Protein (CREB)1 is a transcription factor involved in many physiological processes including the regulation of cell proliferation, apoptosis and cell cycle. Furthermore, an increased expression and activity of CREB was detected in tumors of distinct origin, which are often associated with disease progression and poor prognosis of tumor patients. Own preliminary work demonstrated a correlation between HER-2/neu and CREB expression in in vitro models of HER-2/neu-mediated transformation as well as in HER-2/neu+ mammary carcinoma, which was accompanied by an increased cell growth as well as a reduced apoptosis in vitro and in vivo. Despite CREB-regulated processes have been well characterized, there exist little information about the posttranscriptional control of CREB. In order to identify whether CREB expression can be controlled by CREB regulating microRNAs (miRNAs), the aim of this project is (i) to identify general CREB regulating miRNAs, (ii) characterize the expression, regulation and function of these miRNAs, (iii) to define HER-2/neu regulated CREB regulating miRNAs, (iv) to analyze the clinical relevance of CREB regulating miRNAs and their association with therapy resistance in HER-2/neu+ tumors as well as (v) to determine their modulation as novel therapy concept for HER-2/neu overexpressing tumors. These analyses will not only extend the knowledge of the miRNA-mediated control of CREB expression, but will also give insights into the functional role of the miRNA/CREB/HER-2/neu network, which might lead to the development of innovative strategies for the treatment of therapy naive as well as therapy resistant HER-2/neu overexpressing tumors.