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

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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.