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Gene expression analysis in Interleukin-12-induced suppression of mouse mammary carcinoma.

ABSTRACT: Interleukin-12 (IL-12) has potent antitumor activities via natural killer cells and cytotoxic T lymphocytes. However, the molecular mechanisms whereby IL-12 induces tumoricidal activities are poorly understood. Here, we report the genome-wide analysis of gene expression in a primary murine mammary carcinoma model that resembles human breast cancer, following the therapeutic application of recombinant IL-12, which restricted tumor growth and metastasis. IL-12 was able to curtail neovascularization in the tumor as well as enhance the number of tumor-infiltrating lymphocytes. Comprehensive examination of global gene expression revealed IL-12-induced molecular changes associated with tumor regression and reduced lung metastasis, thus providing a high-resolution snapshot of a host response against a developing malignancy and a rich source of potential targets for therapeutic intervention of breast cancer.

SUBMITTER: Shi X

PROVIDER: S-EPMC2957898 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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Gene expression analysis in Interleukin-12-induced suppression of mouse mammary carcinoma.

Shi Xiaoyan X Liu Jianguo J Xiang Zhaoying Z Mitsuhashi Maki M Wu Rita S RS Ma Xiaojing X

International journal of cancer 20040701 4

Interleukin-12 (IL-12) has potent antitumor activities via natural killer cells and cytotoxic T lymphocytes. However, the molecular mechanisms whereby IL-12 induces tumoricidal activities are poorly understood. Here, we report the genome-wide analysis of gene expression in a primary murine mammary carcinoma model that resembles human breast cancer, following the therapeutic application of recombinant IL-12, which restricted tumor growth and metastasis. IL-12 was able to curtail neovascularizatio ...[more]

PMID: 15122590

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Project description:BackgroundBreast tissue is among the most sensitive tissues to the carcinogenic actions of ionizing radiation and epidemiological studies have linked radiation exposure to breast cancer. Currently, molecular understanding of radiation carcinogenesis in mammary gland is hindered due to the scarcity of in vivo long-term follow up data. We undertook this study to delineate radiation-induced persistent alterations in gene expression in mouse mammary glands 2-month after radiation exposure.MethodsSix to eight week old female C57BL/6J mice were exposed to 2 Gy of whole body ? radiation and mammary glands were surgically removed 2-month after radiation. RNA was isolated and microarray hybridization performed for gene expression analysis. Ingenuity Pathway Analysis (IPA) was used for biological interpretation of microarray data. Real time quantitative PCR was performed on selected genes to confirm the microarray data.ResultsCompared to untreated controls, the mRNA levels of a total of 737 genes were significantly (p<0.05) perturbed above 2-fold of control. More genes (493 genes; 67%) were upregulated than the number of downregulated genes (244 genes; 33%). Functional analysis of the upregulated genes mapped to cell proliferation and cancer related canonical pathways such as 'ERK/MAPK signaling', 'CDK5 signaling', and '14-3-3-mediated signaling'. We also observed upregulation of breast cancer related canonical pathways such as 'breast cancer regulation by Stathmin1', and 'HER-2 signaling in breast cancer' in IPA. Interestingly, the downregulated genes mapped to fewer canonical pathways involved in cell proliferation. We also observed that a number of genes with tumor suppressor function (GPRC5A, ELF1, NAB2, Sema4D, ACPP, MAP2, RUNX1) persistently remained downregulated in response to radiation exposure. Results from qRT-PCR on five selected differentially expressed genes confirmed microarray data. The PCR data on PPP4c, ELF1, MAPK12, PLCG1, and E2F6 showed similar trend in up and downregulation as has been observed with the microarray.ConclusionsExposure to a clinically relevant radiation dose led to long-term activation of mammary gland genes involved in proliferative and metabolic pathways, which are known to have roles in carcinogenesis. When considered along with downregulation of a number of tumor suppressor genes, our study has implications for breast cancer initiation and progression after therapeutic radiation exposure.

Project description:Mouse mammary tumor virus (MMTV) is a betaretrovirus that causes breast cancer in mice. The mouse mammary epithelial cells are the most permissive cells for MMTV, expressing the highest levels of virus upon infection and being the ones later transformed by the virus due to repeated rounds of infection/superinfection and integration, leading eventually to mammary tumors. The aim of this study was to identify genes and molecular pathways dysregulated by MMTV expression in mammary epithelial cells. Towards this end, mRNAseq was performed on normal mouse mammary epithelial cells stably expressing MMTV, and expression of host genes was analyzed compared with cells in its absence. The identified differentially expressed genes (DEGs) were grouped on the basis of gene ontology and relevant molecular pathways. Bioinformatics analysis identified 12 hub genes, of which 4 were up-regulated (Angp2, Ccl2, Icam, and Myc) and 8 were down-regulated (Acta2, Cd34, Col1a1, Col1a2, Cxcl12, Eln, Igf1, and Itgam) upon MMTV expression. Further screening of these DEGs showed their involvement in many diseases, especially in breast cancer progression when compared with available data. Gene Set Enrichment Analysis (GSEA) identified 31 molecular pathways dysregulated upon MMTV expression, amongst which the PI3-AKT-mTOR was observed to be the central pathway down-regulated by MMTV. Many of the DEGs and 6 of the 12 hub genes identified in this study showed expression profile similar to that observed in the PyMT mouse model of breast cancer, especially during tumor progression. Interestingly, a global down-regulation of gene expression was observed, where nearly 74% of the DEGs in HC11 cells were repressed by MMTV expression, an observation similar to what was observed in the PyMT mouse model during tumor progression, from hyperplasia to adenoma to early and late carcinomas. Comparison of our results with the Wnt1 mouse model revealed further insights into how MMTV expression could lead to activation of the Wnt1 pathway independent of insertional mutagenesis. Thus, the key pathways, DEGs, and hub genes identified in this study can provide important clues to elucidate the molecular mechanisms involved in MMTV replication, escape from cellular anti-viral response, and potential to cause cell transformation. These data also validate the use of the MMTV-infected HC11 cells as an important model to study early transcriptional changes that could lead to mammary cell transformation.

Dataset Information

Gene expression analysis in Interleukin-12-induced suppression of mouse mammary carcinoma.

Publications

Gene expression analysis in Interleukin-12-induced suppression of mouse mammary carcinoma.

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