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Virtual screening of the multi-gene regulatory molecular mechanism of Si-Wu-tang against non-triple-negative breast cancer based on network pharmacology combined with experimental validation.
Zhang, Z, Liu, J, Liu, Y, Shi, D, He, Y, Zhao, P
Journal of ethnopharmacology. 2021;:113696
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Si-Wu-Tang (SWT), a prestigious herbal formula from China, has been extensively used for centuries for female-related diseases. It has been documented that SWT has a significant inhibitory effect on non-triple-negative breast cancer (non-TNBC) cells. However, there has been limited comprehensive analysis of the targeted effects of the anticancer components of SWT and its exact biological mechanism. AIM OF THE STUDY This study aims to uncover the mechanism by which SWT treats non-TNBC by applying a network pharmacological method combined with experimental validation. MATERIALS AND METHODS First, SWT compounds were collected from the Traditional Chinese Medicines Systems Pharmacology database (TCMSP) and The Encyclopedia of Traditional Chinese Medicine (ETCM), and then the targets related to SWT were obtained from the TCMSP and SwissTarget databases. Second, a target data set of non-TNBC proteins was established by using the Online Mendelian Inheritance in Man (OMIM), GeneCards and Gene Expression Omnibus (GEO) databases. Third, based on the overlap of targets between SWT and non-TNBC, a protein-protein interaction (PPI) network was built to analyse the interactions among these targets, which focused on screening for hub targets by topology. On these hub genes, we conducted a meta-analysis and survival analysis to screen the best match targets, ESR1, PPARG, CAT, and PTGS2, which had a strong correlation with the ingredients of SWT in our verification by molecular docking. In vitro experiments further proved the reliability of the network pharmacology findings. Finally, FunRich software and the ClusterProfiler package were utilized for the enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data. RESULTS A total of 141 active ingredients and 116 targets of SWT were selected. GO enrichment analysis showed that the biological processes through which SWT acted against non-TNBC (FDR<0.01) mainly involved modulating energy metabolism and apoptosis. According to RT-qPCR and Western blotting, the mRNA and protein expression of ESR1, PPARG and PTGS2 were upregulated (P < 0.01), and the mRNA and protein levels of CAT were downregulated (P < 0.01), suggesting a multi-gene regulatory molecular mechanism of SWT against non-triple-negative breast cancer. CONCLUSIONS This research explored the multi-gene pharmacological mechanism of action of SWT against non-TNBC through network pharmacology and in vitro experiments. The findings provide new ideas for research on the mechanism of action of Chinese medicine against breast cancer.
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Low-Fat Dietary Modification and Risk of Ductal Carcinoma In Situ of the Breast in the Women's Health Initiative Dietary Modification Trial.
Peila, R, Chlebowski, R, Manson, JE, Crane, TE, Lane, DS, Saquib, N, Shadyab, AH, Tabung, FK, Barac, A, Zhang, Z, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021;(9):1753-1756
Abstract
BACKGROUND Results of observational studies of the association between dietary fat and risk of invasive breast cancer have been inconsistent. In the Women's Health Initiative dietary modification (DM) randomized trial designed to lower fat intake, the intervention was not associated with a statistically significant reduction of overall breast cancer risk. However, the DM association with risk of ductal carcinoma in situ (DCIS) of the breast, a putative breast cancer precursor, has not been reported. METHODS A total of 48,835 postmenopausal women, ages 50-79 years at enrollment, with no breast cancer history and ≥32% of total energy intake from fat, were randomly assigned either to a dietary intervention (n = 19,541) designed to reduce total fat intake to 20% of energy and to increase vegetable, fruit, and grain consumption, or to a comparison group (n = 29,294). Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the association between the intervention and DCIS risk. RESULTS During 18.7 years (median) cumulative follow-up, including intervention (∼8.7 years) and post-intervention phases (∼13.0 years), 817 DCIS cases were ascertained. No evidence of an association between the DM intervention and DCIS risk was observed overall, or by trial phase (intervention and post-intervention). Similarly, no associations were found in subgroups defined by potential risk factors for DCIS. CONCLUSIONS DM aiming to reduce fat intake was not associated with altered risk of DCIS. IMPACT These results do not provide evidence of an association between dietary fat reduction and the risk of DCIS among postmenopausal women.
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Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy.
Atwell, LL, Zhang, Z, Mori, M, Farris, P, Vetto, JT, Naik, AM, Oh, KY, Thuillier, P, Ho, E, Shannon, J
Cancer prevention research (Philadelphia, Pa.). 2015;(12):1184-1191
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Abstract
Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention.