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Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.

ABSTRACT: The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) that comprised small interfering RNA (siRNA) complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We used TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor-bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets.

SUBMITTER: Ren Y

PROVIDER: S-EPMC3633234 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.

Ren Yin Y Cheung Hiu Wing HW von Maltzhan Geoffrey G Agrawal Amit A Cowley Glenn S GS Weir Barbara A BA Boehm Jesse S JS Tamayo Pablo P Karst Alison M AM Liu Joyce F JF Hirsch Michelle S MS Mesirov Jill P JP Drapkin Ronny R Root David E DE Lo Justin J Fogal Valentina V Ruoslahti Erkki E Hahn William C WC Bhatia Sangeeta N SN

Science translational medicine 20120801 147

The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specif ...[more]

PMID: 22896676

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Project description:BACKGROUND:Inhibitor of differentiation protein 4 (ID4) is a dominant negative regulator of the basic helix-loop-helix (bHLH) family of transcription factors. During tumorigenesis, ID4 may act as a tumor suppressor or as an oncogene in different tumor types. However, the role of ID4 in breast cancer is not clear where both an oncogenic and a tumor suppressor function have been attributed. Here, we hypothesize that ID4 behaves as both, but its role in breast differs according to the estrogen receptor (ER) status of the tumor. METHODS:ID4 expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and ID4 was assessed using Kaplan-Meier plotter. Correlation between methylation and expression was analyzed using the MEXPRESS tool. In vitro experiments involved ectopic expression of ID4 in MCF-7, T47D, and MDA-MB231 breast cancer cell lines. Migration and colony formation capacity were assessed after transfection treatments. Gene expression was analyzed by ddPCR and methylation by MSP, MS-MLPA, or ddMSP. RESULTS:Data mining analysis revealed that ID4 expression is significantly lower in ER+ tumors with respect to ER- tumors or normal tissue. We also demonstrate that ID4 is significantly methylated in ER+ tumors. Kaplan-Meier analysis indicated that low ID4 expression levels were associated with poor overall survival in patients with ER+ tumors. In silico expression analysis indicated that ID4 was associated with the expression of key genes of the ER pathway only in ER+ tumors. In vitro experiments revealed that ID4 overexpression in ER+ cell lines resulted in decreased migration capacity and reduced number of colonies. ID4 overexpression induced a reduction in ER levels in ER+ cell lines, while estrogen deprivation with fulvestrant did not induce changes neither in ID4 methylation nor in ID4 expression. CONCLUSIONS:We propose that ID4 is frequently silenced by promoter methylation in ER+ breast cancers and functions as a tumor suppressor gene in these tumors, probably due to its interaction with key genes of the ER pathway. Our present study contributes to the knowledge of the role of ID4 in breast cancer.

Dataset Information

Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.

Publications

Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.

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