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Gene expression profiling on mouse models of cardiomyopathies

ABSTRACT: Adjuvant chemotherapy of anthracycline derivatives with antibodies against erbB2 (i.e. trastuzumab, herceptin) is highly effective for a subset of mammary tumors overexpressing erbB2 oncogen. However, an undesired effect of the combined treatment is the increase incidence of dilated cardiomyopathies that may affect a 30% subpopulation of these patients. The accumulating evidence demonstrates the essential role of neuregulin signaling in the adult heart, and morerover, indicates that an impaired neuregulin signaling exacerbates the doxorubicin-mediated cardiac toxicity. Despite this strong evidence, the precise molecular interactions and the specific cardiomyocyte targets of the active erbB2/erbB4 heterodimer remain unknown. In this study, we examined potential molecular targets and mechanisms underlying the synergistic cardiotoxicity of anthracyclines in the ventricular muscle specific erbB4 knockout mouse. We employed a DNA microarray to assess the characteristic gene expression profile, whose partial data was verified by real time RT-PCR and then, grouped in functional categories and pathways. From this study, we demonstrate the upregulation of genes related to the classical signature of a hypertrophic response, shared by the 3 models. In addition, these results revealed an erbB-dependent hypertrophic response through the interaction with G-protein coupled receptors, a commonality in the 3 models. A robust upregulation of EGF and HB-EGF and pleitrophin implicated in cardiac growth together with the remarkable downregulation of IGF-I/PI 3`Kinase pathway characterize the doxorubicin-treated erbB4-KO mice. This defect together with metabolic abnormalities appears to be underlying the phenotypic modification of cardiomyocytes in doxorubicin-treated erbB4-KO mouse.

ORGANISM(S): Mus musculus

PROVIDER: GSE17749 | GEO | 2009/12/12

SECONDARY ACCESSION(S): PRJNA118353

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human cancers underscoring the need to identify new therapeutic vulnerabilities. Previously, we reported high expression of transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 in human PDAC, however their precise role in PDAC formation or progression remains unclear. Here, we have studied PDAC tumor dependency on CtBPs for growth and metastasis using an orthotopic syngeneic pancreatic tumor mouse model. CRISPR-based homozygous deletion of Ctbp2 dramatically decreased PDAC tumor growth, drastically reduced metastatic potential, and significantly prolonged survival. Interrogating differential gene expression of the orthotopic PDAC tumors from CtBP2 WT vs. CtBP2 KO cohorts, we identified significant downregulation of the EGFR-superfamily receptor ErbB3 in CtBP2 KO tumors, and further determined that CtBP regulates expression of both the ErbB2 and 3 EGFR superfamily genes in PDAC cells. We therefore hypothesized that CtBP regulation of physiologic ErbB2/3 signaling contributes, in part, to PDAC growth and metastasis. Indeed, we observed that CtBP2 KO cells exhibited severely attenuated activation of phospho-Akt after neuregulin stimulation of ErbB2/3, and we demonstrate that human PDAC cells also show CtBP dependence of ErbB2/3 expression. Our results suggest that a subset of PDAC tumors is dependent on physiologic ErbB2/3 signaling and could be targeted by pharmacologic inhibitors of ErbB2 and/or ErbB3. Providing proof of concept, the ErbB2-targeted multikinase inhibitor lapatinib, but not the ErbB1/EGFR targeted agent erlotinib, effectively killed ErbB3 expressing PDAC cells, while CtBP2 KO cells where ErbB3 expression was extinguished, were resistant to lapatinib. Taken together, our data suggests that ErBb2/3 targeted therapeutics can effectively target a critical PDAC dependency on physiologic ErbB2/3 signaling which is the result of CtBP’s oncogenic transcriptional program that drives PDAC tumor progression.

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Gene expression profiling on mouse models of cardiomyopathies

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