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MiRNA expression during early, mid and late breast cancer disease progression in mammary glands from MMTV-PyMT transgenic mice

ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in a variety of cellular processes. miRNA dysregulation is recognized to play an essential role in the development and progression of cancer. MMTV-PyMT mice (Jax Strain: FVB/N-Tg(MMTV-PyVT)634Mul/J) are a well-characterized transgenic mouse model of breast cancer. Upon activation of the MMTV-PyVT transgene (mouse mammary tumor virus (MMTV) long terminal repeat upstream of a cDNA sequence encoding the Polyoma Virus middle T antigen (PyVT)) female carriers develop palpable mammary tumors as early as 5 weeks of age. We performed miRNA microarrays on samples from the MMTV-PyMT transgenic mouse model to investigate the differential expression of miRNAs during development of malignant disease in this model.

ORGANISM(S): Mus musculus synthetic construct

PROVIDER: GSE68630 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA283263

REPOSITORIES: GEO

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Project description:Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter driven polyoma middle T oncoprotein (MMTV-PyMT) metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and microRNA (miRNA) expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChipM-BM-. or miRNA 2.0 arrays. Real-time quantitative PCR (qPCR) was used to confirm changes in gene expression. Treatment with DPM beginning at the age of four weeks delayed the onset of palpable lesions, delayed tumor progression and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPMM-bM-^@M-^Ys chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention. MMTV-PyMT+ female mice were randomly divided into a DPM treatment group (n=10 mice, total of 100 glands) and a vehicle (control) group (n=7 mice, total of 70 glands). When mice were four weeks old, when hyperplasia lesions begin to develop in the FVB strain (21), DPM (10 mg/kg) or vehicle was injected IP into the peritoneum of each mouse on a 5 days on/2 days off dosing schedule for a total of 11 weeks (week one=injection one), until mice were 15 weeks of age. Each of the 10 mammary tumors per mouse was monitored until the study end point. A total six breast tumor RNA samples were used for microarray analysis, with three form mice treated with DPM and three from mice treated with vehicle.

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MiRNA expression during early, mid and late breast cancer disease progression in mammary glands from MMTV-PyMT transgenic mice

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