Zinc finger proteins and ATP-binding cassette transporter-dependent multidrug resistance.

BACKGROUND: Multidrug resistance (MDR) remains a significant challenge in cancer treatment, leading to poor clinical outcomes. Dysregulation of ATP-binding cassette (ABC) transporters has been identified as a key contributor to MDR. Zinc finger proteins (ZNPs) are key regulators of transcription and have emerged as potential contributors to cancer drug resistance. Bridging the knowledge gap between ZNPs and MDR is essential to understand a source of heterogeneity in cancer treatment. This review sought to elucidate how different ZNPs modulate the transcriptional regulation of ABC genes, contributing to resistance to cancer therapies. METHODS: The search was conducted using PubMed, Google Scholar, EMBASE and Web of Science. RESULTS: In addition to ABC-blockers, the transcriptional features regulated by ZNP are expected to play a role in reversing ABC-mediated MDR and predicting the efficacy of anticancer treatments. Among the ZNP-induced epithelial to mesenchymal transition, SNAIL, SLUG and Zebs have been identified as important factors in promoting MDR through activation of ATM, NFκB and PI3K/Akt pathways, exposing the metabolism to potential ZNP-MDR interactions. Additionally, nuclear receptors, such as VDR, ER and PXR have been found to modulate certain ABC regulations. Other C2H2-type zinc fingers, including Kruppel-like factors, Gli and Sp also have the potential to contribute to MDR. CONCLUSION: Besides reviewing evidence on the effects of ZNP dysregulation on ABC-related chemoresistance in malignancies, significant markers of ZNP functions are discussed to highlight the clinical implications of gene-to-gene and microenvironment-to-gene interactions on MDR prospects. Future research on ZNP-derived biomarkers is crucial for addressing heterogeneity in cancer therapy.

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.

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.

Stachys schtschegleevii tea, matrix metalloproteinase, and disease severity in female rheumatoid arthritis patients: a randomized controlled clinical trial.

BACKGROUND: Stachys schtschegleevii (SSC) is a herbal medicine used to treat infections. To date, this is the first study aimed to investigate the effects of SSC tea on disease activity score (DAS), serum inflammatory biomarkers and matrix metalloproteinases (MMP-1 and MMP-3) among women with rheumatoid arthritis (RA). METHODS: This pilot, triple-blind, randomized controlled clinical trial was conducted among forty-four women (age: 30-65 years) diagnosed with moderately active RA. Subjects were randomly assigned (1:1 ratio) into either SSC group (2.4 g/day SSC + 2.4 g/day black tea, n=22) or placebo (2.4 g/day black tea, n=22) for 8 weeks. Serum high-sensitivity C-reactive protein (hs-CRP), interleukin-1 beta (IL-1ß), and MMPs were measured using ELISA. According to the American College of Rheumatology guideline considering hs-CRP, DAS28 was assessed. RESULTS: Both study groups had respondent rates above 94.9%. The SSC intervention caused significant reductions in the number and the percent changes of the tender joints (SSC: -74.39% vs. placebo: -57.15%, mean differences= -0.77; P<0.05) and DAS28 [SSC: -32.44% vs. placebo: -22.32%, mean differences= -0.41, P<0.05). Unlike the intervention within SSC group that showed significant reductions in the mean serum levels of hs-CRP, IL-1ß, and MMP-3, SSC caused significant MMP-3 reductions (SSC: -20.59% vs. placebo: 1.29%, P<0.05). CONCLUSION: The SSC intervention showed an appropriate clinical efficacy for female RA patients, accompanying remarkable reductions in the number of tender and swollen joints, DAS28, and serum levels of MMP-3. This can provide additional insights to the interventional studies controlling RA-related pathological and inflammatory outcomes. Trial registration Prospectively registered at the Iranian Registry of Clinical Trials (IRCT), linked to the WHO Registry Network ( https://en.irct.ir/trial/11602 , IRCT registration number: IRCT2015032011335N5, Registration date:2015-05-12). Key Points • Stachys schtschegleevii improved clinical outcomes and attenuated disease severity in RA patients. • Stachys schtschegleevii ameliorated serum level of MMP-3 in RA patients.

Dietary inflammatory index and breast cancer risk: an updated meta-analysis of observational studies.

This updated meta-analysis sought to determine whether the pro-inflammatory potential of diet is a risk factor for breast cancer (BrCa) development, for the first time focusing on the effects of design heterogeneity. The search was performed using Scopus, PubMed, and Embase databases. Data were extracted from twenty-one eligible studies, including eleven cohorts (336,085 participants/20,033 incidence cases), and ten case-control studies (9,833 cases/12,752controls). The random-effect was used to calculate the relative risk (RR) using STATA 16 software. The highest dietary inflammatory index (DII) vs. the lowest category showed 16% increased risk of BrCa (95% CI: 1.06-1.26; I2 = 62.8%, P (I2) < 0.001). This was notable in post-menopausal status (RR = 1.13, 95% CI: 1.04-1.22), women with body mass index (BMI) ≥ 30 kg/m2 (RR = 1.35, 95% CI: 1.07-1.63), and study populations from developing countries (RR = 1.79, 95% CI: 1.12-2.47). Methodological covariates were subject to subgroup meta-analyses and showed stronger results among case-control studies (RR = 1.50, 95% CI: 1.20-1.80), studies considered age-matched controls (RR = 1.56, 95% CI: 1.19-1.93) and hospital-based controls (RR = 2.11, 95% CI: 1.58-2.64), and cohort studies identified by prolong follow-up durations (RR = 1.13, 95% CI: 1.03-1.22). This updated meta-analysis highlighted the pro-inflammatory diet as a risk factor for BrCa, especially among women in post-menopausal status, obese groups, and developing countries. Meta-analysis in methodological subgroups could improve results, less affected by heterogeneity, and suggested subclassification with important implications for future epidemiological designs and even clinical management.

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.

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.

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.

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.

Erratum: Associations between Dietary Allium Vegetables and Risk of Breast Cancer: A Hospital-Based Matched Case-Control Study.

[This corrects the article on p. 292 in vol. 19, PMID: 27721879.].

The Effects of Berberis Vulgaris Juice on Insulin Indices in Women with Benign Breast Disease: A Randomized Controlled Clinical Trial.

The aim of this study was to investigate the effect of Berberis vulgaris (BV) juice consumption on insulin homeostasis, glycemic profiles of patients with benign breast disease (BBD). This parallel design, triple-blind, randomized and placebo controlled clinical trial was conducted on 85 eligible women diagnosed with BBD who recruited from Nour-Nejat hospital, Tabriz, Iran. Participants were randomly allocated into either intervention group who received BV juice (480 mL/day, n = 44) or BV juice placebo at the same time (480 mL/day, n = 41). After a 7 day run-in period, treatments were administered for the duration of 8 weeks. Participants, care givers and those who assessed laboratory analyses were blinded to the assignments (IRCT registry no: IRCT2012110511335N2). The relative treatment effects of BV supplementation showed decreased serum levels of insulin for 19%, C-peptide for 8%, homeostasis model assessment of insulin resistance index (HOMA-IR) for 16% and glucose to insulin ratio for 22% but HOMA-B increased 44% relative to placebo group over 8 weeks BV supplementation. Although these changes were not statistical significant, the mean changes for C-peptide and HOMA-B were significant just after adjusting for baseline data and covariates. Administration of BV juice showed controlling effects on HOMA related indices, consequently might have beneficial effects on insulin signaling-related functions in women with benign breast tumor.

Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes.

BACKGROUND: The option of endocrine therapy in breast cancer remains conventionally promising. OBJECTIVE: We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. METHODS: In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). RESULTS: Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, P< 0.001; sensitivity = 83.0%, specificity = 65.2% and diagnostic odds ratio, DOR = 12.0) and strongly correlated with ER-/PR- conditions (Cramer's V= 0.44, P< 0.001). Methylated PgRb promoter frequently was observed in tumors recognised as ER- or negative ER/PR (77.1%, P< 0.01). Assessment of DNA methylation of ESR1 harbouring methylation at PgRb was a case significantly suggested to be able to detect the lack of ER/PR expressions (55.6%, P< 0.01; sensitivity = 80.6%, specificity = 68.7% and DOR = 8.7). However, methylated PgRb was quite acceptable determinant to contribute with methylated ESR1 to rank tumors as ER-/PR- (64.4%, P< 0.01; sensitivity = 78.0%, specificity = 62.5% and DOR = 6.0). CONCLUSIONS: Despite the methylation status of ESR1 showed preponderant contribution to tumoral phenotypes of ER- and ER-/PR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.

Consumption of Fresh Yellow Onion Ameliorates Hyperglycemia and Insulin Resistance in Breast Cancer Patients During Doxorubicin-Based Chemotherapy: A Randomized Controlled Clinical Trial.

PURPOSE: Doxorubicin has been found to be associated with insulin resistance in animal models. Onion, a so-called functional food, is noted to affect the insulin signaling pathway of diabetes in vitro. To our knowledge, this is the first study to investigate the effects of consuming fresh yellow onions on insulin-related indices compared with a low-onion-containing diet among breast cancer (BC) patients treated with doxorubicin. METHODS: This parallel-design, randomized, triple-blind, controlled clinical trial was conducted on 56 eligible BC patients (aged 30-63 years), diagnosed with invasive ductal carcinoma. Following their second cycle of chemotherapy, subjects were assigned in a stratified-random allocation to receive body mass index-dependent 100 to 160 g/d of onion as high onion group (HO; n = 28) or 30 to 40 g/d small onions in low onion group (LO; n = 28) for 8 weeks intervention. Participants, care givers, and those who assessed laboratory analyses were blinded to the assignments (IRCT Registry No.: IRCT2012103111335N1). RESULTS: The compliance level of participants in the analysis was as high as 87.85%. A total of 23 available cases was analyzed in each group. The daily use of HO resulted in a significant decrease in serum fasting blood glucose and insulin levels in comparison with LO, over the period of study ( P < .001). Posttreatment with HO showed a significant decrease in homeostasis model of assessment-insulin resistance relative to changes in the LO group ( P < .05). A comparison of the changes that occurred throughout pre- and postdose treatments indicated improved quantitative insulin sensitivity check index ( P < .05) and controls on C-peptide in the HO group ( P < .05). CONCLUSIONS: The present study demonstrated the effectiveness of onion to ameliorate hyperglycemia and insulin resistance in BC during doxorubicin-based chemotherapy.

Associations between Dietary Allium Vegetables and Risk of Breast Cancer: A Hospital-Based Matched Case-Control Study.

PURPOSE: The protective effect of Allium vegetables against carcinogenesis has been reported in experimental studies particularly focusing on the gut. Therefore, we conducted a hospital-based matched case-control study to explore the association between dietary Allium consumption and risk of breast cancer among Iranian women in northwest Iran. METHODS: A validated, quantitative, food frequency questionnaire was completed in 285 women (aged 25-65 years old) newly diagnosed with histopathologically confirmed breast cancer (grade II, III or clinical stage II, III) in Tabriz, northwest Iran, and the completed questionnaires were included in an age- and regional-matched hospital based-control study. The odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression models. RESULTS: Multivariate analysis showed that there was a negative association between the consumption of raw onion and risk of breast cancer after adjustment for covariates (OR, 0.63; 95% CI, 0.40-1.00); however, this association was insignificant. On the other hand, there was a positive association between consumption of cooked onion and risk of breast cancer, after adjustment for covariates (OR, 1.54; 95% CI, 1.02-2.32). However, reduced risk of breast cancer was associated with higher consumption of garlic and leek with adjusted ORs of 0.41 (95% CI, 0.20-0.83) and 0.28 (95% CI, 0.15-0.51), respectively. CONCLUSION: Our findings suggest that high consumption of certain Allium vegetables, in particular garlic and leek, may reduce the risk of breast cancer, while high consumption of cooked onion may be associated with an increased risk of breast cancer.

Effects of Fresh Yellow Onion Consumption on CEA, CA125 and Hepatic Enzymes in Breast Cancer Patients: A Double- Blind Randomized Controlled Clinical Trial.

Onion (Allium cepa) consumption has been remarked in folk medicine which has not been noted to be administered so far as an adjunct to conventional doxorubicin-based chemotherapy in breast cancer patients. To our knowledge, this is the first study aimed to investigate the effects of consuming fresh yellow onions on hepatic enzymes and cancer specific antigens compared with a low-onion containing diet among breast cancer (BC) participants treated with doxorubicin. This parallel design randomized controlled clinical trial was conducted on 56 BC patients whose malignancy was confirmed with histopathological examination. Subjects were assigned in a stratified-random allocation into either group received body mass index dependent 100-160 g/d of onion as high onion group (HO; n=28) or 30-40 g/d small onion in low onion group (LO; n=28) for eight weeks intervention. Participants, care givers and laboratory assessor were blinded to the assignments (IRCT registry no: IRCT2012103111335N1). The compliance of participants in the analysis was appropriate (87.9%). Comparing changes throughout pre- and post-dose treatments indicated significant controls on carcinoembryonic antigen, cancer antigen-125 and alkaline phosphatase levels in the HO group (P<0.05). Our findings for the first time showed that regular onion administration could be effective for hepatic enzyme conveying adjuvant chemotherapy relevant toxicity and reducing the tumor markers in BC during doxorubicin-based chemotherapy.

Dietary resistant starch contained foods and breast cancer risk: a case-control study in northwest of Iran.

BACKGROUND: A protective effect of resistant starch (RS) containing foods on carcinogenesis has been shown from several lines of experimental evidence for gastrointestinal cancers. Therefore, we aimed to investigate the association between RS contained foods and breast cancer (BC) risk in a hospital-based, age- and origin- matched, case-control study. MATERIALS AND METHODS: A validated, semi-quantitative, food frequency questionnaire (FFQ) was completed by 306 women newly diagnosed with BC aged 25 to 65 years, and 309 healthy women as matched controls. Odds ratios (ORs) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression models. RESULTS: Reduced BC risk was associated with the highest tertile of whole-wheat bread and boiled potato consumption with adjusted ORs at 0.34 (95%CI: 0.19-0.59) and 0.61 (95%CI: 0.37- 0.99), respectively. Among consumers of whole-wheat bread consumers were considered, the protective role of cereals remained relatively apparent at higher intakes level of fiber rich breads at adjusted models (OR=0.53, 95%CI: 0.28-1.01). Moreover, high intake of legumes was found out to be a significant protective dietary factor against risk of BC development with an OR of 0.01 (95%CI: 0.03-0.13). However, consumption of white bread and biscuits was positively related to BC risk. CONCLUSIONS: Our results show that certain RS containing foods, in particular whole wheat bread, legumes and boiled potato may reduce BC risk, whereas higher intake of white bread and biscuits may be related to increased BC risk.