الفهرس 
Review of LiteratureOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the most common type of cancer among women worldwide. The early diagnosis of BC can widely improve response to treatment and increase survival rates. MicroRNAs (miRNAs) are a class of short non-coding RNAs that regulate gene expression post-transcriptionally. Aberrant expression of miRNAs is associated with various cancers including breast cancer. Circulating miRNAs could act as potential non-invasive diagnostic biomarkers for early diagnosis of breast cancer.
Therefore, this study aimed to evaluate serum expression levels of miR-16, miR-760 and miR-1973 in newly discovered breast cancer and benign breast hyperplasia patients, in addition to explore their clinical utility as potential non-invasive diagnostic biomarkers. Also, this study explains the relation between these miRNAs and the cancer antigen 15.3 (CA-15.3) tumor marker in Egyptian female patients with breast cancer and benign breast hyperplasia.
This study was performed on 160 adult female subjects recruited from the out-patient clinic, National Cancer Institute of Cairo University between November 2018 to July 2019. BC patients were fully diagnosed by clinical and laboratory examinations before conducting the study. Patients who take any treatment, underwent chemo-or radiotherapy, and had any other disease or cancers were excluded from this study.
All participants in this study were divided into three groups: (I) Normal controls. (II) Benign breast hyperplasia patients. (III) Breast cancer patients.
All participants were subjected to determination of:
• Serum concentration of CA15.3 by ELISA.
• Serum expression of microRNAs (mir-16, mir-760 and mir-1973) by Taqman quantitative real time polymerase chain reaction.
The results of the study can be summarized as follow:
• In comparison to the control group, serum CA15.3 was significantly elevated in BC patients (p<0.001). Patients with benign hyperplasia exhibited a borderline significance in serum level of CA15.3 (p=0.06). Whereas serum CA15.3 levels showed a non-significant difference between patients with early stage and controls (p=0.111).
• Compared to the control group, the relative expression of miR-16 was significantly up-regulated in BC patients (p=0.002). While, patients with benign hyperplasia exhibited a non-significant elevation in miR-16 expression level (p=1). While, BC patients showed a significant over-expression level of mir-16 (p=0.001) when compared to benign hyperplasia patients.
• Mir-16 did not show any significant associations with family history, menstruation state, histological grade, stage, lymph node metastasis, receptors status, and molecular subtypes.
• MiR-760 relative expression was significantly up-regulated in BC patients compared to the control group (p=0.03). However, patients with benign breast hyperplasia exhibited a non-significant elevation in miR-760 expression level (p=0.556). Compared to the benign group, BC patients showed a significant up-regulation of mir-760 level (p<0.001). BC patients with early stage displayed a significantly higher expression levels of miR-760 when compared to controls (benign and healthy control groups) (p=0.025).
• Family history, menstruation state, lymph node metastasis, and receptors status, did not differ significantly between low and high miR-760 expression groups. While, subgroup with high expression levels of miR-760 was significantly associated with late stages of the disease (p=0.002) and molecular subtypes (p=0.021).
• Compared to the control group, the relative abundance of miR-1973 was significantly up-regulated in BC patients (p<0.001). In contrast, patients with benign hyperplasia exhibited a non-significant elevation in miR-1973 expression level (p=1). Whereas, BC patients showed a significant over-expression level of miR-1973 (p=0.001) when compared to benign patients. BC patients with early stage displayed a significantly higher expression levels of miR-1973 when compared to controls (benign and healthy control groups) (p<0.001).
• MiR-1973 showed no significant associations with family history, histological grade, stage, lymph node metastasis, receptors status, and molecular subtypes. However, serum expression level of miR-1973 was significantly associated with menstruation state (p=0.010).
• ROC curve of serum CA15.3 concentration showed that CA15.3 had the lowest diagnostic value for BC with an optimal cut-off point of 1.29 U/mL which could yield 82% sensitivity and 46% specificity. ROC curve of serum miR-16 expression level showed that miR-16 had 98% sensitivity, 47% specificity and a cut-off point of 2.54. While, serum miR-760 expression level had 64% sensitivity, 63% specificity and a cut-off point of 1.7 and serum miR-1973 had an optimal cut-off point of 1.1 that is associated with sensitivity and specificity of 90% and 50%, respectively.
• The combination of CA15.3 with mir-16, miR-760 and miR-1973 increased sensitivity and/or specificity values. Where, the combination of CA15.3 with miR-16 showed 74% sensitivity and 70% specificity. While, CA15.3 and miR-760 combination resulted in sensitivity and specificity of 71% and 50%, respectively and the combination with miR-1973 showed 74% sensitivity and 63% specificity.
• Binary logistic regression analyses showed that mir-16, miR-760 and miR-1973 were associated with an increased risk of BC development by 100%, 200% and 130% respectively. This result remained significant after adjusting to the potential confounders such as age, family history, and menstruation state.
• Bioinformatics analysis indicated that BRCA1 was a common predicted target gene for the three miRNAs in humans where they bind to its 3’UTR sequence.
In conclusion, this study indicates that serum levels of miR-16, miR-760 and miR-1973 were up-regulated in BC and might be potential non-invasive diagnostic biomarkers for breast cancer, especially when combined with CA15.3. In addition, this study reveals that the high expression levels of these miRNAs were associated with a higher risk of developing breast cancer. Their mechanism and effect on BRCA1 require more clarification. These miRNAs may be used as therapeutic targets in breast cancer treatment.