Biomarkers For Breast Cancer Screening Research Articles

Combining metabolomics and machine learning to discover biomarkers for early-stage breast cancer diagnosis.

There is an urgent need for better biomarkers for the detection of early-stage breast cancer. Utilizing untargeted metabolomics and lipidomics in conjunction with advanced data mining approaches for metabolism-centric biomarker discovery and validation may enhance the identification and validation of novel biomarkers for breast cancer screening. In this study, we employed a multimodal omics approach to identify and validate potential biomarkers capable of differentiating between patients with breast cancer and those with benign tumors. Our findings indicated that ether-linked phosphatidylcholine exhibited a significant difference between invasive ductal carcinoma and benign tumors, including cases with inconsistent mammography results. We observed alterations in numerous lipid species, including sphingomyelin, triacylglycerol, and free fatty acids, in the breast cancer group. Furthermore, we identified several dysregulated hydrophilic metabolites in breast cancer, such as glutamate, glycochenodeoxycholate, and dimethyluric acid. Through robust multivariate receiver operating characteristic analysis utilizing machine learning models, either linear support vector machines or random forest models, we successfully distinguished between cancerous and benign cases with promising outcomes. These results emphasize the potential of metabolic biomarkers to complement other criteria in breast cancer screening. Future studies are essential to further validate the metabolic biomarkers identified in our study and to develop assays for clinical applications.

Identification and validation of screening models for breast cancer with 3 serum miRNAs in an 11,349 samples mixed cohort.

The study focuses on enhancing breast cancer (BC) prognosis through early detection, aiming to establish a non-invasive, clinically viable BC screening method using specific serum miRNA levels. Involving 11,349 participants across BC, 11 other cancer types, and control groups, the study identified serum biomarkers through feature selection and developed two BC screening models using six machine learning algorithms. These models underwent evaluation across test, internal, and external validation sets, assessing performance metrics like accuracy, sensitivity, specificity, and the area under the curve (AUC). Subgroup analysis was conducted to test model stability. Based on the three serum miRNA biomarkers (miR-1307-3p, miR-5100, and miR-4745-5p), a BC screening model, SM4BC3miR model, was developed. This model achieved AUC performances of 0.986, 0.986, and 0.939 on the test, internal, and external sets, respectively. Furthermore, the SSM4BC model, utilizing ratio scores of miR-1307-3p/miR-5100 and miR-4745-5p/miR-5100, showed AUCs of 0.973, 0.980, and 0.953, respectively. Subgroup analyses underscored both models' robustness and stability. This research introduced the SM4BC3miR and SSM4BC models, leveraging three specific serum miRNA biomarkers for breast cancer screening. Demonstrating high accuracy and stability, these models present a promising approach for early detection of breast cancer. However, their practical application and effectiveness in clinical settings remain to be further validated.

MiRNAs as potential biomarkers in early breast cancer detection: a systematic review.

Breast cancer remains a significant global health challenge, with high incidence and mortality rates. While mammography has contributed to declining mortality, its limitations in sensitivity and specificity for early detection, particularly in distinguishing between pure atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC), highlight the need for more precise tools. Even with core needle biopsy (CNB), conclusive diagnoses often require surgical excision. This underscores the urgency for non-invasive biomarkers to improve early detection and differentiation, potentially reducing invasive procedures. Recent research has shifted focus from mRNA to microRNAs (miRNAs) as promising biomarkers for breast cancer screening. These small non-coding RNAs, which exhibit abnormal expression patterns in breast cancer patients' tissue and serum/plasma, play crucial roles in early breast cancer development by modulating proto-oncogenes or tumor suppressor genes at the post-transcriptional level. Notably, miRNAs such as miR-21, miR-155, and miR-200c are key regulators of cell proliferation and apoptosis, with the potential to distinguish between normal tissue and various stages of breast lesions, including ADH, DCIS, and IDC. Additionally, miRNAs in serum and plasma offer a non-invasive method to differentiate breast cancer stages. This review aims to consolidate current knowledge on early breast lesions and explore the potential of miRNAs as biomarkers for early breast cancer detection, which could enhance risk prediction and reduce reliance on invasive diagnostic procedures.

Exploring the potential of humanin as a biomarker for early breast cancer detection: a study of serum levels and diagnostic performance

Introduction Breast cancer is a leading cause of cancer death in women worldwide, and early detection is crucial for effective treatment. Mitochondrial dysfunction has been linked to cancer development and progression. Humanin, a mitochondrial-derived peptide, has been shown to have cytoprotective effects and may be involved in breast cancer development. In this study, we aimed to investigate the potential of humanin as a biomarker for breast cancer. Methods We recruited 45 female patients diagnosed with primary invasive ductal breast cancer and 45 healthy volunteers. Serum humanin levels were measured using ELISA, and other cancer markers were measured using an Advia Centaur Immunology Analyser. Results Our results showed that serum humanin levels were significantly higher in breast cancer patients than in healthy controls (p = 0.008). ROC curve analysis indicated that humanin could effectively discriminate between patients and healthy individuals, with a sensitivity of 62.5% and a specificity of 77.5%. Conclusion This suggests that humanin may be a potential new biomarker for breast cancer screening and early detection. Further research is needed to fully understand the relationship between humanin and breast cancer and to develop new diagnostic and therapeutic strategies.

Circulating Tumor-Derived Endothelial Cells: An Effective Biomarker for Breast Cancer Screening and Prognosis Prediction.

Background Circulating tumor-derived endothelial cell (CTEC) is a new potential tumor biomarker to be associated with cancer development and treatment efficacy. However, few evidences are available for breast cancer. Methods Eighty-nine breast cancer patients were recruited, and preoperative and postoperative blood samples were collected. Besides, 20 noncancer persons were enrolled as controls. An improved subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) method was adopted to codetect CD31+ aneuploid CTEC and CD31− aneuploid circulating tumor cell (CTC). Then, the clinical significance of CTCs and CTECs on breast cancer screening and prognosis prediction was evaluated and compared. Results The positive rate of CTCs and CTECs in newly diagnosed breast cancer patients was 68.75% and 71.88%. Among detected aneuploid circulating rare cells, CTEC accounts for a greater proportion than CTC in breast cancer patients. CTEC-positive rate and level were significantly higher in breast cancer patients with lymph node metastasis (LNM) than those without LNM (P=0.043), while there was no significant difference in CTC. CTEC (area under the curve, AUC = 0.859) had better performance than CTC (AUC = 0.795) to distinguish breast cancer patients from controls by receiver operator characteristic curve analysis. Preoperative CTEC count ≥ 2 was a significant risk factor for reducing PFS of breast cancer patients. Conclusions CTECs may function as a reliable supplementary biomarker in breast cancer screening and prognosis prediction.

MicroRNA-155 as a potential biomarker for breast cancer screening: a systematic review and meta-analysis

MicroRNA-155 as a potential biomarker for breast cancer screening: a systematic review and meta-analysis

Signal-on electrogenerated chemiluminescence biosensor for ultrasensitive detection of microRNA-21 based on isothermal strand-displacement polymerase reaction and bridge DNA-gold nanoparticles

MicroRNA-21 (miRNA-21) is a promising diagnostic biomarker for breast cancer screening and disease progression. A sensitive and selective strategy for the quantitative determination of miRNA-21 is of great significance in the early diagnosis of cancers. Herein, a novel electrogenerated chemiluminescence (ECL) biosensor was designed for the detection of miRNA-21 with dual signal amplification based on isothermal strand-displacement polymerase reaction (ISDPR) and bridge DNA-gold nanoparticles (AuNPs) nanocomposites. The ECL biosensor was fabricated by self-assembling a thiolated capture probe (SH-CP) on the surface of a gold electrode. The target miRNA-21 initiated the phi29 DNA polymerase-mediated ISDPR, which could generate large numbers of single-stranded DNA (assistant DNA) with accurate and comprehensive nucleotide sequences. The assistant DNA was captured by the SH-CP self-assembled on the Au electrode and further hybridized with bridge DNA-AuNPs nanocomposites, more biotins can be captured on the electrode surface. Afterward, a streptavidin-modified Ru (bpy)32+ complex (SA-Ru) was bound to the bridge DNA-AuNPs nanocomposites via a specific interaction between biotin and streptavidin to produce a strong ECL signal. The ECL intensity was logarithmically proportion to the concentration of target miRNA-21 over a range from 0.01 fM to 10,000 fM with a detection limit of 3.2 aM. The proposed ECL biosensor was successfully applied to detect miRNA-21 in total RNA samples extracted from human breast cancer cells, and it showed great potential for early cancer diagnosis based on miRNA as a biomarker.

RETRACTED: Potential biomarker for breast cancer screening: A systematic review and meta-analysis

RETRACTED: Potential biomarker for breast cancer screening: A systematic review and meta-analysis

Micro RNA based cancer screening by blood test: a review

Context: Circulating microRNA (miRNA) is of great importance to thebiomarker basednon-invasive cancer diagnosis. Objective: To identify circulating biomarkers for cancer screening and its usability with a micro fluidic device for developing an easy to use, cost effective screening tool by way of a blood test. Method: Reviewed published literature for expression of onco-miRNAs and miR-21(microRNA-21) in cancer patients’ serum and their detection methods. Results: miR-21 was chosen as circulating biomarker for breast cancer screening and testeda microfluidic device for breast cancer with 21 breast cancer and 30 healthy volunteers’ blood samples, results concurred with qPCR, the gold standard for quantification. Conclusion: In comparison to mammogram, which is the gold standard for breast cancer screening, microfluidic platform-based blood test for screening can reach a large population at affordable cost.

Target-triggered triple isothermal cascade amplification strategy for ultrasensitive microRNA-21 detection at sub-attomole level

MicroRNA-21 (miR-21) is a promising diagnostic biomarker for breast cancer screening and disease progression, thus the method for the sensitive and selective detection of miR-21 is vital to its clinical diagnosis. Herein, we develop a novel method to quantify miR-21 levels as low as attomolar sensitivity by a target-triggered triple isothermal cascade amplification (3TICA) strategy. An ingenious unimolecular DNA template with three functional parts has been designed: 5′-fragment as the miR-21 recognition unit, middle fragment as the miR-21 analogue amplification unit, and 3′-fragment as the 8–17 DNAzyme production unit. Triggered by miR-21 and accompanied by polymerase-nicking enzyme cascade, new miR-21 analogues autonomously generated for the successive re-triggering and cleavage process. Simultaneously, the 8–17 DNAzyme-contained sequence could be exponentially released and activated for the second cyclic cleavage toward a specific ribonucleotide (rA)-contained substrate, inducing a remarkably amplified generation of HRP-mimicking DNAzyme in the presence of hemin. Finally, the amperometric technique was used to record the catalytic reduction current of 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of H2O2. The increase in the steady-state current was proportional with the increase of the miR-21 concentration from 1 aM to 100 pM. An ultra-low detection limit of 0.5 aM with an excellent selectivity for even discriminating differences between 1-base mismatched target and miR-21 was achieved. This simple and cost-effective 3TICA strategy is promising for the detection of any short oligonucleotides, simply by altering the target recognition unit in the template sequence.

Serum expression levels of microRNA-382-3p, -598-3p, -1246 and -184 in breast cancer patients.

The purpose of the present study was to investigate the serum levels of microRNA (miRNA/miR)-382-3p, -598-3p, -1246 and -184 in breast cancer patients and to assess their feasibility as biomarkers for breast cancer screening. Serum samples were obtained from 100 breast cancer patients and 40 age-matched healthy control subjects in Taizhou Central Hospital (Taizhou, Zhejiang, China) between January 2013 and September 2014. The serum expression levels of miR-382-3p, -598-3p, -1246 and -184 were determined by stem-loop reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were drawn to evaluate the sensitivity and specificity of the serum miRNA expression levels for the screening of breast cancer. miR-382-3p and -1246 were significantly upregulated in the serum of the breast cancer patients, while miR-598-3p and -184 were significantly downregulated. The sensitivity and specificity to detect breast cancer were as follows: miR-382-3p, 52.0 and 92.5%; miR-598-3p, 95.0 and 85.0%; miR-1246, 93.0 and 75.0%; and miR-184, 87.5 and 71.0%, respectively. The expression levels of the four serum miRNAs were not correlated with the patients' clinical stage. In summary, miR-382-3p, -598-3p, -1246 and -184 are all involved in the development of breast cancer, and are promising biomarkers for breast cancer detection.

Role of microRNAs -29b-2, − 155, − 197 and − 205 as diagnostic biomarkers in serum of breast cancer females

Micro-RNAs (miRs) are known to be differentially expressed in the serum of cancer patients and controls, and can thus be used as biomarkers for cancer screening. We detected the expression level of miR-29b-2, 155, 197 and 205 in the serum of female breast cancer patients and healthy controls to detect whether serum level of this chosen micro-RNAs could detect patients with breast cancer and also to detect difference in level of micro-RNAs between non-metastatic cases and metastatic cases, also we tried to detect any relation between level of micro-RNAs and the stage of the tumor, the size of tumor, nodal affection, the presence of metastasis and also the site of metastasis. Serum samples were collected from 130 female patients, 80 with non-metastatic breast cancer, 20 with metastatic breast cancer and 30 healthy controls. Real-time quantitative PCR was used to detect the expression level of miR-29b-2, −155, −197 and −205. The expression level of miR-29b-2, −155, −197 and −205 was significantly increased in the serum of breast cancer patients. miR-29b-2, −155, −197 and −205 may be useful as a blood-based biomarker for breast cancer screening.

Increased circulating microRNA-155 as a potential biomarker for breast cancer screening: a meta-analysis.

The objective of this meta-analysis was to determine the diagnostic accuracy of circulating microRNA-155 (miR-155) for breast cancer (BC). PubMed, Embase, EBSCO (ASP/BSP), Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched up to 30 January 2014 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was employed to assess the quality of the included studies. Meta-analysis were performed in Meta-Disc 1.4 and Stata 12.0. Three studies with total 184 BC patients and 75 control individuals were included in this meta-analysis. All of the included studies are of high quality (QUADAS scores 12 or 13). The summary estimates revealed that the pooled sensitivity is 79% (95% confidence interval (CI): 72%–84%) and the specificity is 85% (95% CI: 75%–92%), for the diagnosis of breast cancer. In addition, the area under the summary ROC curve (AUC) is 0.9217. The current evidence suggests that circulating miR-155 has the potential diagnostic value with a high sensitivity and specificity for BC. More prospective studies on the diagnostic value of circulating miR-155 for BC are needed in the future.

Circulating microRNAs as specific biomarkers for breast cancer detection.

BackgroundWe previously showed microRNAs (miRNAs) in plasma are potential biomarkers for colorectal cancer detection. Here, we aimed to develop specific blood-based miRNA assay for breast cancer detection.Methodology/Principal FindingsTaqMan-based miRNA profiling was performed in tumor, adjacent non-tumor, corresponding plasma from breast cancer patients, and plasma from matched healthy controls. All putative markers identified were verified in a training set of breast cancer patients. Selected markers were validated in a case-control cohort of 170 breast cancer patients, 100 controls, and 95 other types of cancers and then blindly validated in an independent set of 70 breast cancer patients and 50 healthy controls. Profiling results showed 8 miRNAs were concordantly up-regulated and 1 miRNA was concordantly down-regulated in both plasma and tumor tissue of breast cancer patients. Of the 8 up-regulated miRNAs, only 3 were significantly elevated (p<0.0001) before surgery and reduced after surgery in the training set. Results from the validation cohort showed that a combination of miR-145 and miR-451 was the best biomarker (p<0.0001) in discriminating breast cancer from healthy controls and all other types of cancers. In the blind validation, these plasma markers yielded Receiver Operating Characteristic (ROC) curve area of 0.931. The positive predictive value was 88% and the negative predictive value was 92%. Altered levels of these miRNAs in plasma have been detected not only in advanced stages but also early stages of tumors. The positive predictive value for ductal carcinoma in situ (DCIS) cases was 96%.ConclusionsThese results suggested that these circulating miRNAs could be a potential specific biomarker for breast cancer screening.

Serum microRNA-155 as a potential biomarker for breast cancer screening

MicroRNAs (miRs) have been shown to be differentially expressed in the serum of cancer patients and controls, and can thus be used as biomarkers for cancer screening. We detected the expression level of miR-155 in the serum of female breast cancer patients and healthy controls to investigate whether serum miR-155 could discriminate patients with early-stage breast cancer. Serum samples were collected from 20 female patients with newly diagnosed breast cancer and 10 healthy controls. Real-time quantitative PCR was used to detect the expression level of miR-155. The expression level of miR-155 was significantly increased in the serum of breast cancer patients compared with in the serum of normal controls. MiR-155 may be useful as a blood-based biomarker for breast cancer screening.

Biological complexities in radiation carcinogenesis and cancer radiotherapy: impact of new biological paradigms.

Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity). It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation therapy, all these phenomena should be taken into account.

Gene expression profiling identifies Fibronectin 1 and CXCL9 as candidate biomarkers for breast cancer screening.

Background:There is a need to develop blood-based bioassays for breast cancer (BC) screening. In this study, differential gene expression between BC samples and benign tumours was used to identify candidate biomarkers for blood-based screening.Methods:We identified two proteins (Fibronectin 1 and CXCL9) from a gene expression data set that included 120 BC samples and 45 benign lesions. These proteins fulfil the following criteria: differential gene expression between cancer and benign lesion, protein released in the extracellular medium and stable in the serum, commercially available ELISA kit, ELISA accuracy in a feasibility study. Protein concentrations were determined by ELISA. Blood samples were from normal volunteers (n=119) and early BC patients (n=133).Results:Seventy-three per cent of patients had cT1-T2 tumour. Patients had higher CXCL9 and Fibronectin 1 concentrations than volunteers. CXCL9 mean concentration was 851 and 635 pg ml−1 for patients and volunteers respectively (P=0.013). CXCL9 concentration was significantly higher in patients with estrogen receptor (ER)-negative compared with volunteers (P=0.003), data consistent with gene expression profile. Fibronectin 1 mean concentration was 190 μg ml−1 for patients and 125 μg ml−1 for volunteers (P<0.001). Areas under the curve for BC diagnosis were 0.78 and 0.62 for Fibronectin 1 and CXCL9 respectively. A combined score including Fibronectin 1 and CXCL9 dosages presented 53% of sensitivity and 98% of specificity. Similar performances were observed for ER-negative tumours.Conclusions:This study suggests that Fibronectin 1/CXCL9 dosage in serum could screen a significant rate of BC, including ER-negative, and that differential gene expression analysis is a good approach to select candidate biomarkers to set up blood assays cancer screening.

Use of gene expression profiling to identify fibronectin 1 and MIG as candidate biomarkers for breast cancer screening

e22034 Background: There is a need to develop blood-based bioassays for breast cancer screening. We used differential gene expression between breast cancer samples and benign tumors to identify candidate biomarkers for blood-based screening Methods: 3 candidate proteins (Fibronectin 1, CXCL9, Complement Factor B) were identified from a gene expression dataset that included 120 breast cancer samples and 45 benign lesions. Proteins selection was done with these criteria: differential gene expression between cancer and benign lesion, protein released in the extracellular medium (SwissProt), commercially available ELISAkit, accuracy of the ELISA assay in a feasibility study (n=23). Proteins concentrations were determined in blood samples by ELISA. Blood samples were from normal volunteers blood donors (n=119) and early breast cancer patients (n=133). Results: 73% of the patients were cT1-T2 tumour. CA15.3 was within normal range (&lt;30 IU/ml) in 114 patients (86%). Blood concentrations of CXCL9 and Fibronectin 1 were higher in cancer patients as compared to normal volunteers, mean concentration for CXCL9 was 851pg/ml (range 121- 3941) and 635 pg/ml (range 12–4327) in cancer patients and normal volunteers respectively (p=0.013). CXCL9 concentration was significantly higher in patients with ER-negative breast cancer (mean: 999 pg/ml) as compared to normal volunteers (p=0.003), data consistent with gene expression profile. Fibronectin 1 mean concentration was 190 μg/ml (range 11–326) for cancer patients and 125 μg/ml (range 58–212) for normal volunteers (p&lt;0.001). AUC for breast cancer diagnosis were 0.78 and 0.62 for Fibronectin 1 and CXCL9 respectively. A combined score including Fibronectin 1 and CXCL9 dosages presented a sensitivity of 53% and a 98% specificity. Similar performances were observed for ER-negative tumors Conclusions: This study suggests that Fibronectin 1/CXCL9 dosage in serum could screen a significant rate of breast cancer, including ER-negative breast cancer. These data suggest that analysis of differential gene expression is a good approach to select candidate biomarker to set-up blood assays cancer screening. Prospective validation of the combined score, and development of in house ELISA assay for 25 additional proteins are ongoing. No significant financial relationships to disclose.

Autoantibody to Tumor Antigen, Alpha 2-HS Glycoprotein: A Novel Biomarker of Breast Cancer Screening and Diagnosis

We sought to identify a new serum biomarker for breast cancer screening and diagnosis using stepwise proteomic analysis of sera from breast cancer patients to detect the presence of autoantibodies that react with urinary protein. Two-dimensional immunoblotting was done for screening autoimmunogenic tumor antigens in the urine of breast cancer patients. Reactive spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among urinary proteins separated by two-dimensional electrophoresis, 13 spots showed strong reactivity with pooled sera from breast cancer patients or control sera. By mass spectrometry, we identified alpha 2-HS glycoprotein (AHSG) as a tumor antigen. Peripheral blood was obtained from 81 women diagnosed with breast cancer before surgery and 73 female donors without evidence of any malignancy for the individual analysis. In one-dimensional Western blot analysis, AHSG autoantibody was detected in 64 of 81 breast cancer patients (79.1%) and in 7 of 73 controls (9.6%). The sensitivity of this test in breast cancer patients was 79.0%. Our results suggest that AHSG and anti-AHSG autoantibody may be useful serum biomarkers for breast cancer screening and diagnosis.