Abstract
The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G0-G1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu(+) cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics. These data suggest that CREB affects tumor immunogenicity and is a potential target for cancer therapy.
Highlights
Cyclic (c)AMP responsive element binding protein (CREB) is a 43-kDa protein that belongs to the leucine-zipper class of transcription factors, and is activated by multiple signal transduction pathways [1]
CREB binds to the cAMP response element (CRE), thereby recruiting coactivators of the histone acetylase transferase p300 to the promoter of cAMPresponsive genes, which is accompanied by phosphorylation of CREB at Ser133, which is located in the kinase
Altered CREB status in HER-2/neu–overexpressing cells arises from activation of different signal transduction pathways
Summary
Cyclic (c)AMP responsive element binding protein (CREB) is a 43-kDa protein that belongs to the leucine-zipper class of transcription factors, and is activated by multiple signal transduction pathways [1]. It has been recently demonstrated that CREB has a critical role in the induction and maintenance of malignant transformation and pathogenesis of different cancer types, due to inappropriate activation or inactivation of components of the cAMP signaling pathway [4,5,6]. In this context, CREB is often overexpressed in solid tumors of distinct histology, for example, breast cancer and leukemias, when compared with normal adjacent tissues [4, 7], which might be due to downregulation of CREB by inhibitors, such as the inducible cAMP repressor and the microRNA (miRNA, miR) miR-34b [8, 9]. This study characterizes for the first time a direct link between CREB and HER-2/neu expression and activity, and it unravels at least some of the molecular mechanisms by which CREB can contribute to HER-2/neu–mediated cancer development, thereby suggesting the targeting of CREB as a novel strategy for cancer therapy
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