Identification of MicroRNAs as Breast Cancer Prognosis Markers through the Cancer Genome Atlas

Abstract

Breast cancer is the second-most common cancer and second-leading cause of cancer mortality in American women. The dysregulation of microRNAs (miRNAs) plays a key role in almost all cancers, including breast cancer. We comprehensively analyzed miRNA expression, global gene expression, and patient survival from the Cancer Genomes Atlas (TCGA) to identify clinically relevant miRNAs and their potential gene targets in breast tumors. In our analysis, we found that increased expression of 12 mature miRNAs—hsa-miR-320a, hsa-miR-361-5p, hsa-miR-103a-3p, hsa-miR-21-5p, hsa-miR-374b-5p, hsa-miR-140-3p, hsa-miR-25-3p, hsa-miR-651-5p, hsa-miR-200c-3p, hsa-miR-30a-5p, hsa-miR-30c-5p, and hsa-let-7i-5p —each predicted improved breast cancer survival. Of the 12 miRNAs, miR-320a, miR-361-5p, miR-21-5p, miR-103a-3p were selected for further analysis. By correlating global gene expression with miRNA expression and then employing miRNA target prediction analysis, we suggest that the four miRNAs may exert protective phenotypes by targeting breast oncogenes that contribute to patient survival. We propose that miR-320a targets the survival-associated genes RAD51, RRP1B, and TDG; miR-361-5p targets ARCN1; and miR-21-5p targets MSH2, RMND5A, STAG2, and UBE2D3. The results of our stringent bioinformatics approach for identifying clinically relevant miRNAs and their targets indicate that miR-320a, miR-361-5p, and miR-21-5p may contribute to breast cancer survival.

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

“…High expression of miR-30a (-3p and -5p) is significantly associated with reduced RFS and better OS in our patient cohort, in agreement with 2 independent The Cancer Genome Atlas breast cancer datasets (54). Low miR-30a levels were described in aggressive breast cancer cell lines (54), breast cancer patient plasma, and tumor tissue, in association with high stage and decreased RFS and disease-free survival (55,56). The protective effects of miR-30a have been attributed to the downregulation of target genes involved in migration, invasion, apoptosis, and proliferation (57)(58)(59); regulation of epithelial-mesenchymal transition (EMT) by downmodulating vimentin (60); increasing expression of tight-junction proteins claudin 1, 2, and 3 (54); inhibition of cell self-renewal (61); and switching from glycolysis to mitochondrial respiration (62).…”

“…High expression of miR-30a (-3p and -5p) is significantly associated with reduced RFS and better OS in our patient cohort, in agreement with 2 independent The Cancer Genome Atlas breast cancer datasets (54). Low miR-30a levels were described in aggressive breast cancer cell lines (54), breast cancer patient plasma, and tumor tissue, in association with high stage and decreased RFS and disease-free survival (55,56).…”

Candidate diagnostic miRNAs that can detect cancer in prostate biopsy

“…Many miRNAs identified as dysregulated in the present study have also been reported as altered in other cancer types, including breast cancer (miR‐374b‐5p, miR‐429, miR‐200b‐5p, miR‐200b‐3p, miR‐187‐3p, miR‐196a‐5p, miR‐183‐5p, miR‐21‐5p, and miR‐182‐5p); gastric cancer (miR‐374b‐5p, miR‐200c‐3p, miR‐18b‐5p, miR‐196a‐5p, miR‐21‐5p, and miR‐20a‐3p); ovarian cancer (miR‐141‐5p, miR‐182‐5p, miR‐483‐3p, and miR‐200c‐3p); hepatocellular carcinoma (miR‐135a‐5p, miR‐187‐3p, miR‐148a‐5p, miR‐200a‐3p, and miR‐9‐3p); colorectal cancer (miR‐9‐3p, miR‐135a‐5p, miR‐200c‐3p, miR‐200b‐3p, and miR‐182‐5p); thyroid cancer (miR‐7‐5p and miR‐9‐3p); lung cancer (miR‐200b‐5p, miR‐200b‐3p, miR‐9‐5p, miR‐200a‐3p, and miR‐21‐5p); pancreatic cancer (miR‐200b‐3p, miR‐483‐3p, and miR‐183‐5p); chronic lymphocytic leukemia (miR‐4521, miR‐7‐5p, and miR‐182‐5p); Hodgkin lymphoma (miR‐876‐5p); cervical cancer (miR‐429); head and neck squamous cell carcinoma (miR‐200b‐5p); and bladder cancer (miR‐148a‐3p) …”

“…-5p)[39][40][41][42][43][44][45][46] ; gastric cancer (miR-374b-5p, miR-200c-3p, miR-18b-5p, miR-196a-5p, miR-21-5p, and miR-20a-3p)[47][48][49][50][51] ; ovarian cancer (miR-141-5p, miR-182-5p, miR-483-3p, and miR-200c-3p)[52][53][54][55] ; hepatocellular carcinoma (miR-135a-5p, miR-187-3p, miR-148a-5p, miR-200a-3p, and miR-9-3p)[56][57][58][59] ; colorectal cancer…”

Identification of miRNAs Enriched in Extracellular Vesicles Derived from Serum Samples of Breast Cancer Patients

“…The expression of four of the observed DE miRNAs (miR-142-5p, miR-150-5p, miR-320a, and miR-4433b-5p) selected were further validated by RT-qPCR (test phase) in a larger number of samples. These miRNAs have been previously characterized by their oncogenic and/or tumor suppressor function in other types of cancers, including BC [29,45,46], except for miR-4433-5p, that is a new miRNA with no description in cancer so far.…”