WITHDRAWN: In silico and Experimental Analysis of miR-125b-5 and miR-485-5p Expression in Serum of Patients with Breast Cancer

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The association between the inflammatory potential of diet and the risk of histopathological and molecular subtypes of breast cancer in northwestern Iran: Results from the Breast Cancer Risk and Lifestyle study.

BACKGROUND: This study explored the association between diet-associated inflammation and the risk of different molecular subtypes of breast cancer (BrCA) in a large, population-based case-control study conducted in northwestern Iran. METHODS: The study consisted of 1007 women with histopathologically confirmed BrCA and 1004 controls admitted to hospitals in Tabriz, northwestern Iran, for nonneoplastic conditions. Dietary Inflammatory Index scores and energy-adjusted Dietary Inflammatory Index (E-DII) scores, with and without supplements, were computed on the basis of dietary intake collected using a validated 136-item food frequency questionnaire. RESULTS: Women with the highest E-DII scores (quartile 4) versus those with the lowest E-DII scores (quartile 1) showed a significantly increased BrCA risk (odds ratio for quartile 4 vs quartile 1 [ORQ4vsQ1 ], 1.87; 95% confidence interval [CI], 1.42-2.47), particularly for lobular carcinoma (ORQ4vsQ1 , 3.07; 95% CI, 1.34-7.02). Findings were similar for premenopausal women diagnosed with luminal A BrCA (ORQ4vsQ1 , 2.71; 95% CI, 1.74-4.22) or luminal B BrCA (ORQ4vsQ1 , 2.86; 95% CI, 1.39-5.89). Women consuming the most proinflammatory diets were 3 times more likely to have triple-negative BrCA (ORQ4vsQ1 , 3.00; 95% CI, 1.002-8.96) while compared to luminal A BrCA. The BrCA risk for women consuming diets in the highest half of E-DII scores (E-DII > 0) was 59% greater than the risk for those in the lowest half (95% CI, 1.29-1.97). Also, higher E-DII scores that took into account supplements were associated with larger tumor sizes (T3 > 5 cm; P < .05). CONCLUSIONS: A proinflammatory diet, as indicated by higher E-DII scores, appears to increase the risk of BrCA in Iranian women. Large increases in risk were seen in invasive molecular subtypes of BrCA. Anti-inflammatory diets are suggested to prevent the risk of overall BrCA and more aggressive forms of BrCA in particular.

Dietary patterns in association with the expression of pro-metastatic genes in primary breast cancer.

PURPOSE: Metastasis is a major leading cause of mortality in female breast cancer (BrCa). Cellular motility is a pathological process of metastasis remarked by the overexpression of cortactin (CTTN), Ras homolog family member-A (RhoA), and Rho-associated kinase (ROCK) genes. Their balance is responsible for upholding the integrity of healthy epithelial cell junctions. This study aimed to explore the associations between a posteriori dietary patterns and the expression levels of pro-metastatic genes in primary BrCa. METHODS: In this consecutive case series, 215 eligible women, newly diagnosed with histologically confirmed non-metastatic BrCa (stage I-IIIA), were recruited from Hospitals in Tabriz, Northwestern Iran (2015-2017). The tumoral expression levels of genes were quantified using real-time reverse transcription-polymerase chain reaction. Dietary data assessment was carried out using a validated food frequency questionnaire. RESULTS: Three dietary patterns were identified using principal component analysis (KMO = 0.699). Adherence to the "vegan" pattern (vegetables, fruits, legumes, nuts, seeds, and whole grains) was inversely associated with the expression levels of RhoA (ORAdj.T3vs.T1 = 0.24, 95%CI 0.07-0.79) and ROCK (ORAdj.T3vs.T1 = 0.26, 95%CI 0.08-0.87). In addition, the highest adherence to the "prudent" pattern (spices, seafood, dairy, and vegetable oils) decreased the odds of overexpressions at RhoA (ORAdj.T3vs.T1 = 0.26, 95%CI 0.08-0.84) and ROCK genes (ORAdj.T3vs.T1 = 0.29, 95%CI 0.09-0.95). The highest adherence to "Western" pattern (meat, processed meat, hydrogenated fat, fast food, refined cereals, sweets, and soft drinks) was a risk factor associated with the overexpression of RhoA (ORAdj.T3vs.T1 = 3.15, 95%CI 1.12-8.85). CONCLUSION: Adherence to healthy dietary patterns was significantly associated with the downregulation of pro-metastatic genes. Findings provided new implications to advance the nutrigenomic knowledge to prevent the odds of over-regulations in pro-metastatic genes of the primary BrCa.

Effects of Spectral Envelope and Fundamental Frequency Shifts on the Perception of Foreign-Accented Speech.

To investigate the role of spectral pattern information in the perception of foreign-accented speech, we measured the effects of spectral shifts on judgments of talker discrimination, perceived naturalness, and intelligibility when listening to Mandarin-accented English and native-accented English sentences. In separate conditions, the spectral envelope and fundamental frequency (F0) contours were shifted up or down in three steps using coordinated scale factors (multiples of 8% and 30%, respectively). Experiment 1 showed that listeners perceive spectrally shifted sentences as coming from a different talker for both native-accented and foreign-accented speech. Experiment 2 demonstrated that downward shifts applied to male talkers and the largest upward shifts applied to all talkers reduced the perceived naturalness, regardless of accent. Overall, listeners rated foreign-accented speech as sounding less natural even for unshifted speech. In Experiment 3, introducing spectral shifts further lowered the intelligibility of foreign-accented speech. When speech from the same foreign-accented talker was shifted to simulate five different talkers, increased exposure failed to produce an improvement in intelligibility scores, similar to the pattern observed when listeners actually heard five foreign-accented talkers. Intelligibility of spectrally shifted native-accented speech was near ceiling performance initially, and no further improvement or decrement was observed. These experiments suggest a mechanism that utilizes spectral envelope and F0 cues in a talker-dependent manner to support the perception of foreign-accented speech.

Unsupervised repetition enables rapid perceptual learning.

This study examined how listeners disambiguate an auditory scene comprising multiple competing unknown sources and determine a salient source. Experiment 1 replicated findings from McDermott, Wrobleski, and Oxenham. [(2011). Proc. Natl. Acad. Sci. U. S. A. 108(3), 1188-1193] using a multivariate Gaussian model to generate mixtures of two novel sounds. The results showed that listeners were unable to identify either sound in the mixture despite repeated exposure unless one sound was repeated several times while being mixed with a different distractor each time. The results support the idea that repetition provides a basis for segregating a single source from competing novel sounds. In subsequent experiments, the previous identification task was extended to a recognition task and the results were modeled. To confirm the repetition benefit, experiment 2 asked listeners to recognize a temporal ramp in either a repeating sound or non-repeating sounds. The results showed that perceptual salience of the repeating sound allowed robust recognition of its temporal ramp, whereas similar features were ignored in the non-repeating sounds. The response from two neural models of learning, generalized Hebbian learning and anti-Hebbian learning, were compared with the human listener results from experiment 2. The Hebbian network showed a similar response pattern as for the listener results, whereas the opposite pattern was observed for the anti-Hebbian output.

Food frequency questionnaire is a valid assessment tool of quercetin and kaempferol intake in Iranian breast cancer patients according to plasma biomarkers.

In epidemiological and clinical studies, the most common nutritional tool to assess dietary flavonol intake is the food frequency questionnaire (FFQ), which needs to contain a detailed list of plant-based foods and be previously validated. Our study aimed to assess the accuracy of dietary flavonol (quercetin, kaempferol, and isorhamnetin) intake from a food frequency questionnaire (FFQ) compared to fasting plasma flavonol concentrations, as biomarkers of exposure, in breast cancer patients. In a consecutive case series, newly diagnosed patients with breast cancer (n = 140) were recruited at Nour-Nejat Hospital, Tabriz, Iran. Flavonol intake was assessed using a validated FFQ. Plasma flavonol concentrations were measured using high-performance liquid chromatography-ultraviolet detection. The accuracy of dietary status was evaluated using a receiver operating characteristic (ROC) and area under the ROC curve (AUC). Dietary status was shown in dichotomous using ROC-cutoff point. The plasma concentrations of quercetin were moderately correlated with dietary intake of quercetin (Spearman's correlation coefficient (rs) = 0.188, P < .05; rpartial= 0.330, P < .01) and plasma concentrations of isorhamnetin (rs = 0.337, P < .001). A linear correlation between dietary levels and plasma concentrations of kaempferol was attained (rpartial = 0.240, P < .05). Using a ROC-cutoff of 61.9 nmol/L for plasma quercetin (test reference), we were able to differentiate between lower and higher consumers of quercetin with an AUCROC-based reference =0.65 (P < .01, sensitivity = 61.8%, and specificity = 60.0%). Using a plasma kaempferol concentration of 60.1 nmol/L (ROC-cutoff), it was possible to detect significant differences between higher and lower intakes of kaempferol (AUCROC-based reference = 0.64, P < .05). The correlations and diagnostic performance with plasma concentrations could present a significant accuracy rate (validity), which seems acceptable for a nutritional questionnaire (FFQ) to assess intakes intake levels of quercetin and kaempferol. An improvement in the accuracy of the flavonol exposure can provide more precise relationship with health outcomes, which may increase their clinical significance.

Profiling the expression of pro-metastatic genes in association with the clinicopathological features of primary breast cancer.

BACKGROUND: Metastasis accounts for ninety percent of breast cancer (BrCa) mortality. Cortactin, Ras homologous gene family member A (RhoA), and Rho-associated kinase (ROCK) raise cellular motility in favor of metastasis. Claudins (CLDN) belong to tight junction integrity and are dysregulated in BrCa. Thus far, epidemiologic evidence regarding the association of different pro-metastatic genes with pathological phenotypes of BrCa is largely inconsistent. This study aimed to determine the possible transcriptional models of pro-metastatic genes incorporate in holding the integrity of epithelial cell-cell junctions (CTTN, RhoA, ROCK, CLDN-1, CLDN-2, and CLDN-4), for the first time, in association with clinicopathological features of primary BrCa. METHODS: In a consecutive case-series design, 206 newly diagnosed non-metastatic eligible BrCa patients with histopathological confirmation (30-65 years) were recruited in Tabriz, Iran (2015-2017). Real-time RT-PCR was used. Then fold changes in the expression of target genes were measured. RESULTS: ROCK amplification was associated with the involvement of axillary lymph node metastasis (ALNM; ORadj. = 3.05, 95%CI 1.01-9.18). Consistently, inter-correlations of CTTN-ROCK (ß = 0.226, P < 0.05) and RhoA-ROCK (ß = 0.311, P < 0.01) were determined among patients diagnosed with ALNM+ BrCa. In addition, the overexpression of CLDN-4 was frequently observed in tumors identified by ALNM+ or grade III (P < 0.05). The overexpression of CTTN, CLDN-1, and CLDN-4 genes was correlated positively with the extent of tumor size. CTTN overexpression was associated with the increased chance of luminal-A positivity vs. non-luminal-A (ORadj. = 1.96, 95%CI 1.02-3.77). ROCK was also expressed in luminal-B BrCa tumors (P < 0.05). The estrogen receptor-dependent transcriptions were extended to the inter-correlations of RhoA-ROCK (ß = 0.280, P < 0.01), ROCK-CLDN-2 (ß = 0.267, P < 0.05), and CLDN-1-CLDN-4 (ß = 0.451, P < 0.001). CONCLUSIONS: For the first time, our findings suggested that the inter-correlations of CTTN-ROCK and RhoA-ROCK were significant transcriptional profiles determined in association with ALNM involvement; therefore the overexpression of ROCK may serve as a potential molecular marker for lymphatic metastasis. The provided binary transcriptional profiles need more approvals in different clinical features of BrCa metastasis.

Rapid adaptation to non-native speech is impaired in cochlear implant users.

To examine difficulties experienced by cochlear implant (CI) users when perceiving non-native speech, intelligibility of non-native speech was compared in conditions with single and multiple alternating talkers. Compared to listeners with normal hearing, no rapid talker-dependent adaptation was observed and performance was approximately 40% lower for CI users following increased exposure in both talker conditions. Results suggest that lower performance for CI users may stem from combined effects of limited spectral resolution, which diminishes perceptible differences across accents, and limited access to talker-specific acoustic features of speech, which reduces the ability to adapt to non-native speech in a talker-dependent manner.

Study of long non-coding RNA highly upregulated in liver cancer (HULC) in breast cancer: A clinical & in vitro investigation.

Background & objectives: Breast cancer remains the most common malignancy among women worldwide. Long non-coding RNAs (lncRNAs) have been shown to play critical roles in tumour initiation and progression. This study was aimed to evaluate the potential role of lncRNA highly upregulated in liver cancer (HULC) in breast cancer. Methods: The expression of HULC was evaluated in breast cancer patients and cell lines using real-time quantitative reverse transcription polymerase chain reaction. Small interfering RNA-based knockdown was also employed to study the potential role of HULC in breast cancer cell lines including ZR-75-1, MCF7 and MDA-MB-231. Results: HULC was significantly upregulated in tumour tissues compared to non-tumoural margins (P <0.001). The receiver operating characteristic (ROC) curve analysis demonstrated the biomarker potential of HULC (ROCAUC=0.78, P <0.001). The HULC knockdown induced apoptosis and suppressed cellular migration in breast cancer cell lines. Interpretation & conclusions: Our results indicated that HULC was upregulated in breast cancer and might play a role in tumourigenesis. The HULC may have a potential to be exploited as a new biomarker and therapeutic target in breast cancer.

miR-140 and miR-196a as Potential Biomarkers in Breast Cancer Patients.

OBJECTIVE: MiR-140 and miR-196a were known to be correlated with cancer diagnosis and prognosis. The current study aimed at the analysis of miR-140 and miR-196a expression patterns and their clinical significance for breast cancer (BC) patients. METHODS: Differentially expressed miR-140 and miR-196a were examined via quantitative PCR in 110 cases of BC and their adjacent non-tumor (ANT) tissues. RESULTS: The results indicated that miR-140 and miR-196a, respectively, notably decreased and increased expression in BC samples in comparison with ANT (p<0.001). Reduced miR-140 expression was also related to Lymph node metastasis (LNM, P= 0.023) and stage (P = 0.009). Additionally, Receiver Operating Characteristics (ROC) analysis illustrated that miR-140 had a significant diagnostic accuracy for stage and LNM of BC patients. We also discovered a strong negative correlation between miR-196a expression with histological grade (P = 0.038), LNM (P = 0.012) and stage (P = 0.001). CONCLUSION: Overall, exploring the miR-140 and miR-196a profiles not only can statistically different among BC and ANT samples, but it is also expected to become potential BC biomarkers.
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Dietary patterns and relative expression levels of PPAR-γ, VEGF-A and HIF-1α genes in benign breast diseases: case-control and consecutive case-series designs.

We aimed to study dietary patterns in association with the relative expression levels of PPAR-γ, vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) in women with benign breast disease (BBD). The study design was combinative, included a case-series and case-control compartments. Initially, eligible BBD patients (n 77, aged 19-52 years old) were recruited at Nour-Nejat hospital, Tabriz, Iran (2012-2014). A hospital-based group of healthy controls was matched for age (n 231, aged 20-63 years old) and sex. Dietary data were collected using a valid 136-item FFQ. Principal component analysis generated two main components (Kaiser-Meyer-Olkin = 0·684), including a Healthy pattern (whole bread, fruits, vegetables, vegetable oils, legumes, spices, seafood, low-fat meat, skinless poultry, low-fat dairy products, nuts and seeds) and a Western pattern (starchy foods, high-fat meat and poultry, high-fat dairy products, hydrogenated fat, fast food, salt and sweets). High adherence to the Western pattern increased the risk of BBD (ORadj 5·59; 95 % CI 2·06, 15·10; P < 0·01), whereas high intake of the Healthy pattern was associated with a 74 % lower risk of BBD (95 % CI 0·08, 0·81; P < 0·05). In the BBD population, the Western pattern was correlated with over-expression of HIF-1α (radj 0·309, P < 0·05). There were inverse correlations between the Healthy pattern and expressions of PPAR-γ (radj -0·338, P < 0·05), HIF-1α (radj -0·340, P < 0·05) and VEGF-A (radj -0·286, P < 0·05). In conclusion, new findings suggested that the Healthy pattern was associated inversely with the risk of BBD, and this could be correlated with down-regulation of PPAR-γ, VEGF-A and HIF-1α genes, which might hold promise to preclude BBD of malignant pathological transformation.

Coenzyme Q10 in association with metabolism-related AMPK/PFKFB3 and angiogenic VEGF/VEGFR2 genes in breast cancer patients.

Low levels of coenzyme Q10 (CoQ10) have been reported in the circulation of patients with breast cancer, particularly in metastatic features. Our objective was to study the correlation between plasma levels of CoQ10 and the tumoral expression levels of AMPK, PFKFB3, VEGF, and VEGFR2. This study was a part of consecutive case series conducted on 100 women with newly diagnosed invasive ductal breast carcinoma, with an age range of 30-60 years. Plasma levels of CoQ10 were measured using HPLC coupled to an UV detector. The expression levels were quantified using quantitative real-time PCR. Structural equation modeling (SEM) was applied to generate pathways describing gene-to-gene inter-correlations. Using SEM identified AMPK expression to contribute positively to VEGF-A/VEGFR2 ratio (coefficient b = 0.64, P < 0.001). The VEGFR2 expression positively correlated with tumor size (coefficient b = 0.31, P < 0.001). A linear correlation between expression levels of AMPK and PFKFB3 was observed (rAdj = - 0.273, P = 0.02). Similarly, VEGF-A was correlated with VEGFR2 (rAdj = 0.698, P < 0.001). There were inverse significant correlations between CoQ10 and the fold changes of AMPK (rAdj = - 0.276, P = 0.030), VEGF-A (rAdj = - 0.319, P = 0.011) and VEGFR2 (rAdj = - 0.262, P = 0.045). The correlation between CoQ10 and the fold changes of PFKFB3 was significantly progesterone receptor (PR) dependent (rAdj = - 0.284, P = 0.041). Plasma CoQ10 was correlated with VEGF-A in hormone receptor-dependent mode (ER + : rAdj = - 0.286, P = 0.032 and PR + : rAdj = - 0.313, P = 0.025). Our findings could provide new insights suggesting CoQ10 can inversely correlate to the expression levels of VEGF-A/VEGFR2 as angiogenic factors and AMPK/PFKFB3 as biomarkers for tumoral glycolysis, especially in a hormone receptor-dependent manner to possibly prevent the progression of breast carcinogenesis.

Association of Omentin-1 with Oxidative Stress and Clinical Significances in Patients with Breast Cancer.

Purpose: Breast cancer (BC) is globally the main reason of cancer-related deaths in women. Omentin-1, an anti-inflammatory and antioxidant adipokine, plays different roles in tumorigenesis and anti-oncogenic pathways. In present study, we investigated the association of omentin-1 with oxidative stress and clinical significances in healthy controls and BC patients to assess the prognostic and diagnostic value of omentin-1 in this cancer. Methods: This case-control study included 88 BC patients and 86 healthy controls. The serum levels of omentin-1 were assessed by enzyme-linked immunosorbent assays methods. Also, total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde (MDA) serum levels were measured by spectrophotometer. quantitative real-time polymerase chain reaction (qRT-PCR) was applied to the measurement of gene expression of omentin-1. Results: the serum levels of omentin-1 were significantly lower in the BC patients compared to the healthy controls (P<0.001). Moreover, gene expression of omentin-1was significantly downregulated in the BC tissues compared to the adjacent normal tissues (P<0.001). Gene expression of omentin-1and its serum levels were significantly higher in grade I compared with grade II and III (P=0.001, P<0.001, respectively). Additionally, the serum levels of omentin-1 in the p53-positive BC patients were significantly higher than the p53-negative BC patients (P=0.001). There was an inverse correlation between the serum levels of MDA and TOS with the serum levels of omentin-1 (r=-0.436, r=-461, respectively). Conclusion: We conclude that omentin-1 may have a good prognostic and diagnostic roles in the BC patients and decreases oxidative stress in these patients.

Effects of cholecalciferol supplementation on serum angiogenic biomarkers in breast cancer patients treated with tamoxifen: A controlled randomized clinical trial.

OBJECTIVE: The aim of this study was to investigate the effects of cholecalciferol supplementation on serum levels of angiogenic parameters in patients with breast cancer (BC) who were treated with tamoxifen. METHODS: This was a pilot-based, randomized, triple-blind, placebo-controlled clinical trial with 52 patients with BC randomly assigned to either an intervention group receiving weekly 50 000 IU cholecalciferol or a placebo group for 8 wk. At baseline and at end of study, serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang)-2, hypoxia-inducible factor (Hif)-1, and high-sensitivity C-reactive protein were measured by enzyme-linked immunosorbent assay. Every 4 wk, a completed 3-d, 24-h dietary record and daily sunlight exposure checklist were collected and anthropometric variables were measured. RESULTS: The ultimate number of participants in each arm was 22 for analyses. For premenopausal women, cholecalciferol supplementation resulted in a significant decrease in serum levels of Ang-2 and VEGF-A after 8 wk of treatment (P < 0.05). In the absence of vascular invasion, supplementation led to a significant decrease in Ang-2 levels compared with the placebo group (P < 0.05). Supplementation caused significant increases in Hif-1 in patients diagnosed with the infiltration of tumors into vascular or lymphatic vessels (P < 0.05). CONCLUSION: Cholecalciferol supplementation achieved sufficient efficacy among patients with BC taking tamoxifen and could be effective in the reduction of angiogenic biomarkers particularly dependent on the infiltration status of the tumor to vessels. Further studies with larger subgroups should be investigated.

The effects of Berberis vulgaris consumption on plasma levels of IGF-1, IGFBPs, PPAR-γ and the expression of angiogenic genes in women with benign breast disease: a randomized controlled clinical trial.

BACKGROUND: The present study was designed to investigate the effects of Berberis vulgaris (BV) juice consumption on plasma levels of insulin-like growth factor (IGF-1), IGF-binding proteins (IGFBPs), and the expression of PPAR-γ, VEGF and HIF in women with benign breast disease. METHODS: This parallel design randomized, double-blind controlled clinical trial was conducted on 85 eligible patients diagnosed with benign breast disease. They were assigned randomly into either BV juice group (n = 44, BV juice: 480 ml/day) or placebo group (n = 41, BV placebo juice: 480 ml/day) for 8 weeks intervention. Participants, caregivers and those who assessed laboratory analyses were blinded to the assignments. Plasma levels of biomarkers were measured at baseline and after 8 weeks by ELISA. Quantitative real-time PCR was used to measure the fold change in the expression of each interested gene. RESULTS: The compliance of participants was 95.2% and 40 available subjects analyzed in each group at last. Relative treatment (RT) effects for BV juice caused 16% fall in IGF-1 concentration and 37% reduction in the ratio of IGF-1/1GFBP1. Absolute treatment effect expressed 111 ng/ml increased mean differences of IGFBP-3 between BV group and placebo. Plasma level of PPAR-γ increased in both groups but it was not significant. Fold changes in the expressions of PPAR-γ, VEGF and HIF showed down-regulation in the intervention group compared to placebos (P < 0.05). CONCLUSIONS: The BV juice intervention over 8 weeks was accompanied by acceptable efficacy and decreased plasma IGF-1, and IGF-1/IGFBP-1 ratio partly could be assigned to enhanced IGFBP-1 level in women with BBD. The intervention caused reductions in the expression levels of PPAR, VEGF, and HIF which are remarkable genomic changes to potentially prevent breast tumorigenesis. TRIAL REGISTRATION: IRCT2012110511335N2. Registered 10 July 2013 (retrospectively registered).

The contribution of dietary and plasma folate and cobalamin to levels of angiopoietin-1, angiopoietin-2 and Tie-2 receptors depend on vascular endothelial growth factor status of primary breast cancer patients.

The aim of this study was to determine the association of dietary folate and cobalamin with plasma levels of Angiopoietins (ANG), vascular endothelial growth factor-C (VEGF-C) and tyrosine kinase receptor-2 (Tie-2) of primary breast cancer patients. Women (n = 177), aged 30 to 75 years diagnosed with breast cancer were recruited from an ongoing case series study. Dietary intake of nutrients was estimated by using a validated food frequency questionnaire. Enzyme-linked immunosorbent assay was applied to measure biomarkers. MCF-7 cell cultures were supplemented with folic acid (0-40 µM) for 24 h to measure cell viability and fold change of expression by the real-time reverse transcriptase-polymerase chain reaction. Structural equation modeling was applied to analyze the structural relationships between the measured variables of nutrients and Angiopoietins. Dietary intake of folate and cobalamin showed a significant inverse correlation with plasma ANG-1 and ANG-2 (P < 0.05), particularly in subjects with estrogen-receptor positive tumors or low plasma VEGF-C. Plasma folate was positively associated with the ratio of ANG-1/ANG-2 (P < 0.05). Residual intake levels of total cobalamin were inversely associated with plasma ANG-1 when plasma stratum of VEGF-C was high (P < 0.05). Structural equation modeling identified a significant inverse contribution of folate profiles on the latent variable of Angiopoietins (coefficient ß = -0.99, P < 0.05). Folic acid treatment resulted in dose-dependent down-regulations on ANGPT1 and ANGPT1/ANGPT2 ratio but VEGF and ANGPT2/VEGF were upregulated at folic acid >20 µM. Studying the contributing role of dietary folate to pro-angiogenic biomarkers in breast cancer patients can infer the preventive role of folate in the ANGs/VEGF-C-dependent cascade of tumor metastasis. By contrast, high concentrations of folic acid in vitro supported VEGF-C-dependent ANGPT2 overexpression might potentiate micro-lymphatic vessel development to support malignant cell dissemination.

Circulating miR-21 and miR-155 as potential noninvasive biomarkers in Iranian Azeri patients with breast carcinoma.

BACKGROUND: Breast cancer (BC) is the most common cause of cancer-related mortality among women. Despite recent advances in diagnosis and prognosis of breast carcinomas, noninvasive biomarkers have been poorly identified. We evaluated the biomarker potential of miR-21 and miR-155 in tissue and plasma specimens of Iranian Azeri patients. MATERIALS AND METHODS: Tumor specimens, paired nontumoral adjacent tissues, and matched plasma samples were collected from a number of thirty Iranian Azeri women with breast carcinoma. Plasma of healthy women was used as the control. The relative expression of miR-21 and miR-155 was measured by real-time polymerase chain reaction. RESULTS: Our data revealed that the expression levels of miR-21 and miR-155 in tumor tissues are significantly higher than paired nontumoral adjacent specimens (P < 0.05). Furthermore, receiver operating characteristic (ROC) curve analysis of samples showed the area under the ROC curve of 0.81 for miR-21 and area of 0.83 for miR-155. In addition, statistical analysis showed that miR-21 and miR-155 RNAs are significantly detected in the plasma of BC patients compared to healthy specimens (P < 0.05). Circulating miRNAs yielded area under the ROC curve of 0.99 for miR-21 and 0.92 for miR-155. CONCLUSION: Our data showed that miR-21 and miR-155 oncomiRs can be considered as noninvasive biomarkers for monitoring breast carcinomas. However, further investigations are needed to confirm the use of these noncoding RNAs in pathology.

Dietary protein sources and tumoral overexpression of RhoA, VEGF-A and VEGFR2 genes among breast cancer patients.

BACKGROUND: High protein intake may promote angiogenesis giving support to the development of metastasis according to the experimental data. However, nutritional epidemiologic evidence is inconsistent with metastasis. Therefore, we aimed to study the association between dietary intake of protein and tumoral expression levels of Ras homologous gene family member A (RhoA), vascular endothelial growth factor-A (VEGF-A), and VEGF receptor-2 (VEGFR2) in primary breast cancer (BC) patients. METHODS: Over this consecutive case series, 177 women primary diagnosed with histopathologically confirmed BC in Tabriz (Iran) were enrolled between May 2011 and November 2016. A validated food frequency questionnaire was completed for eligible participants. Fold change in gene expression was measured using quantitative real-time PCR. Principal component factor analysis (PCA) was used to express dietary groups of proteins. RESULTS: Total protein intake was associated with the expression level of VEGF-A in progesterone receptor-positive (PR+: ß = 0.296, p < 0.01) and VEGFR2 in patients with involvement of axillary lymph node metastasis (ALNM+: ß = 0.295, p < 0.01) when covariates were adjusted. High animal protein intake was correlated with overexpression of RhoA in tumors with estrogen receptor-positive (ER+: ß = 0.230, p < 0.05), ALNM+ (ß = 0.238, p < 0.05), and vascular invasion (VI+: ß = 0.313, p < 0.01). Animal protein intake was correlated with the overexpression of VEGFR2 when tumors were positive for hormonal receptors (ER+: ß = 0.299, p < 0.01; PR+: ß = 0.296, p < 0.01). Based on the PCA outputs, protein provided by whole meat (white and red meat) was associated inversely with RhoA expression in ALNM+ (ß = - 0.253, p < 0.05) and premenopausal women (ß = - 0.285, p < 0.01) in adjusted models. Whole meat was correlated with VEGFR2 overexpression in VI+ (ß = 0.288, p < 0.05) and premenopausal status (ß = 0.300, p < 0.05) in adjusted models. A group composed of dairy products and legumes was correlated with the overexpression of RhoA (ß = 0.249, p < 0.05) and VEGF-A (ß = 0.297, p < 0.05) in VI+. CONCLUSIONS: Based on the multivariate findings, the dietary protein could associate with the overexpression of RhoA and VEGF-VEGFR2 in favor of lymphatic and vascular metastasis in BC patients.

Clinical and in vitro Study of Novel Long Non-Coding RNA lncUSMycN in Breast Cancer

Background: Despite recent advances in diagnosis and treatment, breast cancer remains a leading cause of death in women worldwide. Long non-coding RNAs are a new class of RNA molecules that have been shown to participate in tumorigenesis. The aim of this study was to investigate the expression of lncUSMycN in tumor samples and to evaluate its potential role in the breast cancer cell line. Methods: Real-time polymerase chain reaction was employed to assess lncUSMycN expression in breast tumor tissues and cancer cell lines. Furthermore, small interfering RNA was used to knockdown lncUSMycN. Results: The data showed the significant up-regulation of lncUSMycN in tumor tissues compared to non-tumor specimens (95% CI, p = 0.002). Receiver operating characteristic (ROC) curve analysis demonstrated the biomarker potential of lncUSMycN (ROCAUC = 0.70, p < 0.001) for invasive breast ductal carcinoma. Furthermore, lncUSMycN knockdown induced apoptosis and suppressed cellular migration in breast cancer cells (p < 0.01). Conclusion: The findings highlight the pivotal role of lncUSMycN in tumorigenesis, providing a new potential target for breast cancer therapy.

A new insight on serum microRNA expression as novel biomarkers in breast cancer patients.

Breast cancer (BC) is one of the widespread lethal diseases affecting a large number of women worldwide. As such, employing and identifying significant markers for detecting BC in different stages can assist in better diagnosis and management of the disease. Several diverse markers have been introduced for diagnosis, but their limitations, including low specificity and sensitivity, reduce their application. microRNAs (miRNAs), as short noncoding RNAs, have been shown to significantly influence gene expression in different disease pathologies, especially BC. Clearly, among different samples used for detecting miRNA expressions, circulating miRNAs present as promising and useful biomarkers. Among different body fluid samples, serum serves as one of the most reliable samples, thanks to its high stability under various severe conditions and some unique features. Extensive research has suggested that BC-related miRNAs can remain stable in the serum. The objective of this review is to describe different samples used for detecting miRNAs in BC subjects with emphasis on serum miRNAs. So, this study highlights serum miRNAs with the potential of acting as biomarkers for different stages of BC. We reviewed the possible correlation between potential miRNAs and the risk of early breast cancer, metastatic breast cancer, response to chemotherapy, and relapse.