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Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs.

ABSTRACT: Objective:To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression of microRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negative breast cancers. Methods:FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNP rs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) were used to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. Results:Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs (miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739 genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping and microRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymph nodes (P < 0.05) in the risk group (A allele). Conclusions:We present two novel methods to analyze SNPs within 3'UTRs that use: (i) a single miRNA marker expression and (ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these two methods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to the rs4245739 variant in ER-negative breast cancer.

SUBMITTER: Anwar SL

PROVIDER: S-EPMC5785168 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs.

Anwar Sumadi Lukman SL Wulaningsih Wahyu W Watkins Johnathan J

Cancer biology & medicine 20171101 4

<h4>Objective</h4>To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression of microRNAs and subsequent <i>MDM4</i> expression and the correlation of these factors with clinical determinants of ER-negative breast cancers.<h4>Methods</h4>FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNP rs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atla ...[more]

PMID: 29372105

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Project description:Development of aromatase inhibitor resistant breast cancer among postmenopausal women continues to be a major clinical obstacle. Previously, our group demonstrated that as breast cancer cells transition from hormone-dependent to hormone-independent, they are associated with increased growth factor signaling, enhanced cellular motility, and the epithelial to mesenchymal transition (EMT). Given the complexity of cancer stem cells (CSC) and their implications on endocrine resistance and EMT, we sought to understand their contribution towards the development of aromatase inhibitor resistant breast cancer. Cells cultured three dimensionally as mammospheres are enriched for CSCs and more accurately recapitulates tumors in vivo. Therefore, a global proteomic analysis was conducted using letrozole resistant breast cancer cells (LTLT-Ca) mammospheres and compared to their adherent counterparts. Results demonstrated over 1000 proteins with quantitative abundance ratios were identified. Among the quantified proteins, 359 were significantly altered (p < 0.05), where 173 were upregulated and 186 downregulated (p < 0.05, fold change >1.20). Notably, midasin, a chaperone protein required for maturation and nuclear export of the pre-60S ribosome was increased 35-fold. Protein expression analyses confirmed midasin is ubiquitously expressed in normal tissue but is overexpressed in lobular and ductal breast carcinoma tissue as well as ER+ and ER- breast cancer cell lines. Functional enrichment analyses indicated that 19 gene ontology terms and one KEGG pathway were over-represented by the down-regulated proteins and both were associated with protein synthesis. Increased midasin was strongly correlated with decreased relapse free survival in hormone independent breast cancer. For the first time, we characterized the global proteomic signature of CSC-enriched letrozole-resistant cells associated with protein synthesis, which may implicate a role for midasin in endocrine resistance.

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Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs.

Publications

Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs.

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