A review of prognostic and predictive biomarkers in breast cancer

Clinical and Experimental Medicine - Breast cancer (BC) is a common cancer all over the world that affects women. BC is one of the leading causes of cancer mortality in women, which today has...     

TMPRSS3 is a novel poor prognostic factor for breast cancer

It has recently been reported that transmembrane protease, serine 3 (TMPRSS3) is overexpressed in cancer. However, TMPRSS3 expression and its biological roles in breast cancer (BC) have not been reported. This study aims to investigate the TMPRSS3 expression in BC and its relation with the outcome of the BC. This study involves a total of 149 BC tissues and adjacent non-cancerous tissues that were diagnosed between 2004 and 2007. Immunohistochemistry is used to compare the pattern of TMPRSS3 expression in BC and in adjacent non-cancerous tissues. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of TMPRSS3 expression among BC patients. The results are as follow: TMPRSS3 expression is significantly in BC compared to adjacent non-cancerous tissues. High TMPRSS3 expression was related to TNM stage, lymph node metastasis, and Ki-67 expression. Furthermore, the overall survival (OS) and disease-free survival (DFS) in BC patients with high TMPRSS3 expression were lower than those in patients with low TMPRSS3 expression. Based on multivariate analysis, lymph node metastasis, TNM stage and TMPRSS3 expression are independent prognostic factors for OS in BC, while lymph node metastasis and TMPRSS3 expression are independent prognostic factors for DFS in BC. This study proves that TMPRSS3 expression is an independent prognostic factor for BC patients. Bioinformatic analysis of potential TMPRSS3 binding proteins revealed that TMPRSS3 could be a key regulator of cancer pathways. This study helps us better understand the function of TMPRSS3 in cancer.     

The modulatory role of dendritic cell-T cell cross-talk in breast cancer: Challenges and prospects

Antigen recognition and presentation are highlighted as the first steps in developing specialized antigen responses. Dendritic cells (DCs) are outstanding professional antigen-presenting cells (APCs) responsible for priming cellular immunity in pathological states, including cancer. However, the diminished or repressed function of DCs is thought to be a substantial mechanism through which tumors escape from the immune system. In this regard, DCs obtained from breast cancer (BC) patients represent a notably weakened potency to encourage specific T-cell responses. Additionally, impaired DC-T-cell cross-talk in BC facilitates the immune evade of cancer cells and is connected with tumor advancement, immune tolerance, and adverse prognosis for patients. In this review we aim to highlight the available knowledge on DC-T-cell interactions in BC aggressiveness and show its therapeutic potential in BC treatment.     

Increased levels of erythropoietin in nipple aspirate fluid and in ductal cells from breast cancer patients.

BACKGROUND: Erythropoietin (Epo) is an important regulator of erythropoiesis, and controls proliferation and differentiation of both erythroid and non-erythroid tissues. Epo is actively synthesized by breast cells during lactation, and also plays a role in breast tissues promoting hypoxia-induced cancer initiation. Our aims are to perform an exploratory investigation on the Epo accumulation in breast secretions from healthy and cancer patients and its localization in breast cancer cells. METHODS: Epo was determined by ELISA, immunoprecipitation, western blot and immunocytochemical analyses in 130 Nipple Aspirate Fluids (NAF) from 102 NoCancer and 28 Breast Cancer (BC) patients, comparing results with those found in 10 milk, 45 serum samples and breast cancer cell lines. RESULTS: Epo levels in NAFs were significantly higher than those in milk and serum. No difference in Epo electrophoretic mobility was found among NAF, milk and serum samples, and conditioned cell culture medium. Immunolocalization of intracellular Epo in ductal cells floating in BC NAFs was similar to those of cancer cell lines. No significant correlation between TNM classification and Epo in NAFs from BC patients was found. Significantly higher Epo concentration was found in NAF from BC patients compared to NoCancer. CONCLUSION: We demonstrate that breast epithelial cells are a source of Epo in breast microenvironment, suggesting the presence of a paracrine/autocrine Epo function in NAFs, triggering off intracellular signaling cascade with subsequent BC initiation.     

Circulating soluble levels of MIF in women with breast cancer in the molecular subtypes: relationship with Th17 cytokine profile

Clinical and Experimental Medicine - Breast cancer (BC) is a health problem worldwide; there is evidence that inflammatory cytokines are increased in BC. Macrophage migration inhibitory factor...     

MiR-337-3p suppresses migration and invasion of breast cancer cells by downregulating ESRP1

Breast cancer (BC) is a common malignant tumor in women, and a considerable number of studies show that aberrant expression of miRNA is correlated with BC development. By analyzing TCGA-BRCA database through bioinformatics method, this study disclosed that miR-337−3p was significantly low in BC tissue and might be a cancer inhibitor in BC. To explore the effect and potential mechanism of miR-337−3p in BC, qRT-PCR was used in this study to indicate that the expression of miR-337−3p was downregulated in BC cells. Then, the effects of miR-337−3p on BC cells were detected by western blot, Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays. After upregulating miR-337−3p expression, the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) of BC cells were markedly inhibited while cell apoptosis remarkably increased. Besides, it was predicted and identified by bioinformatics analysis and dual-luciferase assay that ESRP1 was a target gene of miR-337−3p. Finally, the progression and EMT of BC cells were promoted after upregulating ESRP1 expression level. However, upregulating miR-337−3p as well as ESRP1 reduced the promotion on the malignant phenotype of BC cells. This result revealed that miR-337−3p could inhibit ESRP1 expression to perform its biological functions. In conclusion, it was illustrated in this study that miR-337−3p is a tumor-inhibitor of BC and plays its regulatory role via its downstream gene ESRP1.     

Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France

The prevalence of BRCA1/2 germ-line mutations was assessed in a prospective population-based series of early-onset breast cancer (BC) patients in France, and the usefulness of a clinical assessment of hereditary BC risk, based on multiple criteria including pedigree structure, was evaluated. Through the Rhone region BC registry, 232 women diagnosed with BC before 46 years of age were included. They were tested for BRCA1/2 mutations an average of 10 months after diagnosis. All the women were classified according to their family history of cancer: high risk of hereditary breast cancer (HBC), low risk of HBC, isolated BC, and unknown HBC risk. Deleterious mutations were observed in 21 women (9.1%): 15 (6.5%) BRCA1 and 6 (2.6%) BRCA2. Mutations were more prevalent in women who developed BC before age 41 than in women who developed BC between ages 41 and 45 (12.8% versus 5.2%, respectively, P = 0.04). A high prevalence of BRCA1/2 mutations was found among women in the high-risk category with particular family features (i.e., small family size, predominantly male pedigree, specific cancers; 23.5%) and among women with isolated BC before age 41 and with five or fewer close adult female relatives (16.6%). According to the 10% probability level recommended by the American Society of Clinical Oncology guidelines for genetic testing of cancer, BRCA1/2 mutation screening should be considered for all women diagnosed before age 41, except for those with isolated BC in a large pedigree including multiple unaffected female relatives. The clinical assessment of HBC risk that we have developed should help in the decision to perform genetic testing.     

Use of artificial neural networks in modeling associations of discriminant factors: towards an intelligent selective breast cancer screening.

In order to improve the costs/benefits ratio of breast cancer (BC) screenings, the author evaluated the performance of a back-propagation artificial neural network (ANN) to predict an outcome (cancer/not cancer) to be used as classificator. Networks were trained on data from familial history of cancer, and sociodemographic, gynecoobstetric and dietary variables. The ANN achieved up to 94.04% of positive predictive value and 97.60% of negative predictive value. Results could operate as guidelines for preselecting women who would be considered as a BC high-risk subpopulation. The procedure--not only based on age factor, but on a multifactorial basis--appears to be a promising method of achieving a more efficient detection of preclinical, asymptomatic BC cases.     

Association between genetic variants at 9p21 locus with risk of breast cancer: A systematic review and meta-analysis

Breast cancer (BC) is the most frequent tumor in women and genetic factors are among the main risk factors contributing to this malignancy. Chromosome 9p21 contains important regulatory non-coding RNAs and is associated with multiple malignancies including BC. The current meta-analysis aimed to investigate the association between genetic variants within the 9p21 locus and risk of breast cancer. A literature search was performed using PubMed, Web of Science, Embase, MEDLINE, Scopus and Clinical key databases. Nine studies containing 23,726 subjects were eligible for the final analysis and specific odds ratios (OR) and confidence intervals (95% CI) were evaluated to assess the strength of the associations. In the pooled analysis, there was an association between the genetic variations in 9p21 locus (CDKN2A/2B) with risk of breast cancer with a standard OR of 1.22 (95% CI: 1.04–1.45, P = 0.016; random-effects model), supporting the significance of this locus as a novel risk factor for breast cancer patients. In conclusion, our results showed that 9p21 region is positively associated with risk of BC and its polymorphisms may be a candidate marker for BC susceptibility.     

Estradiol increases ER-negative breast cancer metastasis in an experimental model

Breast cancer (BC) is the most common cancer affecting women in the United States and metastatic breast cancer is the leading cause of death. The role estradiol plays in ER-positive BC is well-documented, but the way it contributes to ER-negative BC remains unclear. In the present study, we utilized an experimental model of BC metastasis into lung by injecting ER-negative murine 4T1 cells into mice via the lateral tail vein. A 56 % metastasis occurrence rate following the injection of 5 × 10³ cells was observed, thus this cell number was selected to study the potential stimulatory effect of estradiol on ER-negative BC metastasis. Female ovariectomized mice were randomized into estradiol and control groups with 16 mice per group, and estradiol pellets were implanted subcutaneously in the estradiol group. Results demonstrated that estradiol accelerated BC metastasis as indicated by bioluminescent imaging. In addition, estradiol enhanced metastatic tumor colony formation and increased the size of tumor nodules in the lungs, which were due, in part, to the increase in proliferative cells in the metastatic tumors. In vitro, estradiol increased the motility and invasion of 4T1 cells, and the stimulatory effect on cell motility was not blocked by ICI 182, 780, confirming that ER was not involved in the process. Results from the present study suggest that estradiol plays a role in ER-negative BC metastasis in whole animals.     

New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with microRNAs

The neuropeptide substance P (SP) triggers a variety of tumor-promoting signaling pathways through the activation of neurokinin-1receptor (NK1R), a class of neurokinin G protein-coupled receptors superfamily. Recent researches in our and other laboratories have shown the overexpression of both SP and NK1R in breast cancer (BC) patients. SP/NK1R signaling is strongly implicated in the pathogenesis of BC through affecting cell proliferation, migration, metastasis, angiogenesis, and resistance. Therefore, SP/NK1R signaling responses must be rigorously regulated; otherwise, they would contribute to a more aggressive BC phenotype. Recently, microRNAs (miRNAs) as a specific class of epigenetic regulators have been shown to regulate NK1R and thus, controlling SP/NK1R signaling responses in BC. This review summarizes the current knowledge of the role of SP/NK1R signaling and its therapeutic potentials in BC. We also provide an overview regarding the effects of miRNA-mediated NK1R regulatory mechanisms in controlling BC tumorigenesis to gain a clearer view and thus better management of cancer.     

Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.     

Longitudinal Gompertzian analysis of breast cancer mortality in the U.S., 1962-1987: demonstration of a disorder displaying complex deterministic mortality dynamics.

Age-adjusted mortality rates for breast cancer (BC) in the United States from 1962 to 1987 were subjected to longitudinal Gompertzian analysis. Age-adjusted BC mortality rate distributions for women display two distinct Gompertzian slopes. Between age 15 and 40 years, age-adjusted BC mortality rate distributions intercepted at age 33.5 years and mortality rate (per 100,000) 5.83. Between age 50 and 85 years, age-adjusted BC mortality rate distributions intercepted at age 60.4 years and mortality rate 77.0. These two distinct Gompertzian regions correspond to the clinical and biological classification of BC into pre- and post-menopausal varieties. The observation that postmenopausal BC increases in environments conducive to survival and that premenopausal BC increases in environments that are less favorable becomes understandable when BC mortality dynamics are viewed from a competitive and deterministic perspective.     

环状RNA在乳腺癌中作用的研究进展

环状RNA(circRNA)是一类具有环状结构且广泛存在的非编码RNA,具有多样性、特异性、保守性和稳定性等特征.作为新兴的非编码调控分子,circRNA主要通过竞争性内源RNA的机制来调控乳腺癌(BC)细胞增殖和转移,并且参与了多种化学药物治疗耐药、影响疗效.阐明circRNA在BC中的功能与机制,将有助于为BC的诊...     

Decreased serum miR-181a is a potential new tool for breast cancer screening

Breast cancer (BC) screening is important for early detection, but conventional tumor markers lack the desired sensitivity. Aberrant microRNA (miRNA) expression plays an important role in tumor formation and development. Thus, serum miRNAs represent potential BC biomarkers. microRNA-181a (miR-181a) is deregulated in many types of human cancer and is a key oncogenic regulator, but the relationship between serum miR-181a and BC diagnosis has not been investigated. This study investigated serum miR-181a levels in BC patients and healthy controls and compared the diagnostic value of serum miR-181a as a BC tumor marker with the conventional tumor markers CA153 and CEA. Serum miR-181a and miR-16 (as a control) were quantified by real-time quantitative RT-PCR in 20 plasma samples. The promising results prompted analysis of 227 additional samples. The levels of CA153 and CEA were measured using electrochemiluminescence assays. Median miR-181a levels were significantly lower in patients with BC compared to healthy controls (P=0.001). ROC analysis demonstrated the sensitivity and specificity of miR-181a for BC diagnosis at 70.7 and 59.9%, respectively, whereas the sensitivities of CA153 and CEA were 10.53 and 9.21%. As a tumor marker, serum miR-181a expressed a higher level of sensitivity [55.28% (68/123)] in the early stage of BC diagnosis (ductal carcinoma in situ, TNM I and II) than the CA153 and CEA markers (8.13 and 7.32%, respectively). There were no significant associations between miR-181a levels and other clinicopathological parameters. These results suggest that serum miR-181a may represent a novel biomarker for primary BC as well as for early stage BC diagnosis. In combination with other markers, serum miR-181a may improve the sensitivity of BC screening.     

Monoisotopic silver nanoparticles-based mass spectrometry imaging of human bladder cancer tissue: Biomarker discovery

PurposeBladder cancer (BC) is the 10th most common form of cancer worldwide and the 2nd most common cancer of the urinary tract after prostate cancer, taking into account both incidence and prevalence.Materials/methodsTissues from patients with BC and also tissue extracts were analyzed by laser desorption/ionization mass spectrometry imaging (LDI-MSI) with monoisotopic silver-109 nanoparticles-enhanced target (¹⁰⁹AgNPET).ResultsUnivariate and multivariate statistical analyses revealed 10 metabolites that differentiated between tumor and normal tissues from six patients with diagnosed BC. Selected metabolites are discussed in detail in relation to their mass spectrometry (MS) imaging results. The pathway analysis enabled us to link these compounds with 17 metabolic pathways.ConclusionsAccording to receiver operating characteristic (ROC) analysis of biomarkers, 10 known metabolites were identified as the new potential biomarkers with areas under the curve (AUC) higher than >0.99. In both univariate and multivariate analysis, it was predicted that these compounds could serve as useful discriminators of cancerous versus normal tissue in patients diagnosed with BC.