Hsa-miR-375/RASD1 signaling predicts local control in early breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156873 | GEO | 2021/01/01
REPOSITORIES: GEO
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Project description:Purpose of the current study was to identify miRs that can differentiate between patients with and without local relapse after breast conserving therapy in early stage breast cancer, which is especially important in the context of individualized treatment selection. The study was conducted in a pilot and a validation phase. First, 32 patients were screened for the most de-regulated miRs in a panel of 1250 miRs by microarray technology. Second, the candidate miRs were analyzed in an independent cohort of 115 patients using reverse transcription quantitative polymerase chain reaction (RT-qPCR).
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Project description:In order to characterize the various subtypes of breast cancer more precisely and improve patients selection for breast conserving therapy (BCT), molecular profiling has gained importance over the past two decades. MicroRNAs, which are small non-coding RNAs, can potentially regulate numerous downstream target molecules and thereby interfere in carcinogenesis and treatment response via multiple pathways. The aim of the current two-phase study was to investigate whether hsa-miR-375-signaling through RASD1 could predict local control (LC) in early breast cancer. The patient and treatment characteristics of 81 individuals were similarly distributed between relapse (n = 27) and control groups (n = 54). In the pilot phase, the primary tumors of 28 patients were analyzed with microarray technology. Of the more than 70,000 genes on the chip, 104 potential hsa-miR-375 target molecules were found to have a lower expression level in relapse patients compared to controls (p-value < 0.2). For RASD1, a hsa-miR-375 binding site was predicted by an in silico search in five mRNA-miRNA databases and mechanistically proven in previous pre-clinical studies. Its expression levels were markedly lower in relapse patients than in controls (p-value of 0.058). In a second phase, this finding could be validated in an independent set of 53 patients using ddPCR. Patients with enhanced levels of hsa-miR-375 compared to RASD1 had a higher probability of local relapse than those with the inverse expression pattern of the two markers (log-rank test, p-value = 0.069). This two-phase study demonstrates that hsa-miR-375/RASD1 signaling is able to predict local control in early breast cancer patients, which-to our knowledge-is the first clinical report on a miR combined with one of its downstream target proteins predicting LC in breast cancer.
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Project description:A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer.Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value?=?0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p?=?0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value?=?0.000195 HR?=?0.76, 95 % CI 0.66-0.88; corrected p value?=?0.005).Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor ? (ER-?)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted.
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Project description:Hsa-miR-375/RASD1 signaling predicts local control in early breast cancer
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