The effects of oenothein B(OEB) on the proliferation, apoptosis, invasion, and migration of breast cancer MCF-7 and MDA-MB-231 cells were investigated by cell culture in vitro, network pharmacology, and molecular docking. In vitro cell experiments revealed that OEB inhibited the proliferation and colony formation ability, and promoted the apoptosis and formation of apoptotic bodies in breast cancer cells, as well as inhibited the invasion and migration of breast cancer cells. The targets of OEB were obtained using SwissTargetPrediction database and breast cancer targets were obtained from GeneCards. The targets of OEB and breast cancer were entered separately in Venny 2.1 software to obtain the Venn diagram of common targets of OEB and breast cancer. The common targets of OEB and breast cancer were input into STRING database to construct a protein-protein interaction(PPI) network, which was entered into Cytoscape 3.7.2 software for network topology analysis. Key targets were screened according to protein association strength, and analyzed for KEGG pathway enrichment. Molecular docking of OEB to key targets using AutoDock software revealed that OEB stably bound to the active pocket of P53, while OEB promoted the expression of P53 protein. MCF-7 and MDA-MB-231 cell viability and migration ability increased after silencing P53, and this change was reversed after treatment with OEB. Therefore, this study showed that OEB inhibited the proliferation, migration, and invasion of breast cancer MCF-7 and MDA-MB-231 cells, and promoted the apoptosis of breast cancer MCF-7 and MDA-MB-231 cells, which may be related to the targeted regulation of P53.
Humans ; Female ; Cell Proliferation ; Breast Neoplasms/drug therapy* ; Tumor Suppressor Protein p53/genetics* ; Molecular Docking Simulation

BACKGROUND: Breast cancer (BC) is a common malignancy with highly female incidence. So far the function of notoginsenoside R1 (NGR1), the extract from Panax notoginseng, has not been clearly elucidated in BC. METHODS: Optimal culture concentration and time of NGR1 were investigated by cell counting kit-8 assay. Cell proliferation ability was measured by colony formation assays. Transwell assay was used to detect the effect of NGR1 on cell migration and invasion. The apoptosis rate of cells between each group was measured by TUNEL assay. RESULTS: NGR1 treatment has an inhibitory effect on proliferation, migration, invasion, and angiogenesis and a stimulating effect on cell cycle arrest and apoptosis of Michigan Cancer Foundation-7 (MCF-7) cells. The 50% growth inhibitory concentration for MCF-7 cells at 24 h was 148.9 mmol/L. The proportions of MCF-7 cells arrested in the G0/G1 phase were 36.94±6.78%, 45.06±5.60%, and 59.46±5.60% in the control group, 75, and 150 mmol/L groups, respectively. Furthermore, we revealed that NGR1 treatment attenuates BC progression by targeted downregulating CCND2 and YBX3 genes. Additionally, YBX3 activates phosphatidylinositol 3-phosphate kinase (PI3K)/protein kinase B (Akt) signaling pathway by activating kirsten rat sarcoma viral oncogene, which is an activator of the PI3K/Akt signaling pathway. CONCLUSION These results suggest that NGR1 can act as an efficacious drug candidate that targets the YBX3/PI3K/Akt axis in patients with BC.
Animals ; Apoptosis ; Breast Neoplasms/drug therapy* ; Cell Proliferation ; Cyclin D2 ; Female ; Ginsenosides/therapeutic use* ; Humans ; Phosphatidylinositol 3-Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; Rats

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.
Humans ; Immunotherapy ; Molecular Targeted Therapy ; Triple Negative Breast Neoplasms/genetics*

Precision oncology aims to offer the most appropriate treatments to cancer patients mainly based on their individual genetic information. Genomics has provided numerous valuable data on driver mutations and risk loci; however, it remains a formidable challenge to transform these data into therapeutic agents. Transcriptomics describes the multifarious expression patterns of both mRNAs and non-coding RNAs (ncRNAs), which facilitates the deciphering of genomic codes. In this review, we take breast cancer as an example to demonstrate the applications of these rich RNA resources in precision medicine exploration. These include the use of mRNA profiles in triple-negative breast cancer (TNBC) subtyping to inform corresponding candidate targeted therapies; current advancements and achievements of high-throughput RNA interference (RNAi) screening technologies in breast cancer; and microRNAs as functional signatures for defining cell identities and regulating the biological activities of breast cancer cells. We summarize the benefits of transcriptomic analyses in breast cancer management and propose that unscrambling the core signaling networks of cancer may be an important task of multiple-omic data integration for precision oncology.
Female ; Gene Expression Profiling ; Genomics ; Humans ; MicroRNAs ; metabolism ; Precision Medicine ; RNA Interference ; RNA, Messenger ; metabolism ; Triple Negative Breast Neoplasms ; classification ; genetics ; metabolism ; therapy

BACKGROUND: Autophagy plays a crucial role in chemotherapy resistance of triple-negative breast cancer (TNBC). Hence, autophagy-related gene 5 (ATG5), an essential molecule involved in autophagy regulation, is presumably associated with recurrence of TNBC. This study was aimed to investigate the potential influence of single-nucleotide polymorphisms in ATG5 on the disease-free survival (DFS) of early-stage TNBC patients treated with anthracycline- and/or taxane-based chemotherapy. METHODS: We genotyped ATG5 SNP rs473543 in a cohort of 316 TNBC patients treated with anthracycline- and/or taxane-based chemotherapy using the sequenom's MassARRAY system. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to analyze the association between ATG5 rs473543 genotypes and the clinical outcome of TNBC patients. RESULTS: Three genotypes, AA, GA, and GG, were detected in the rs473543 of ATG5 gene. The distribution of ATG5 rs473543 genotypes was significantly different between patients with and without recurrence (P = 0.024). Kaplan-Meier survival analysis showed that patients carrying A allele of ATG5 rs473543 had an increased risk of recurrence and shorter DFS compared with those carrying the variant genotype GG in rs473543 (P = 0.034). In addition, after adjusting for clinical factors, multivariate Cox regression analyses revealed that the AA/GA genotype of rs473543 was an independent predictor for DFS (hazard risk [HR], 1.73; 95% confidence interval [CI], 1.04-2.87; P = 0.034). In addition, DFS was shorter in node-negative patients with the presence of A allele (AA/GA) than in those with the absence of A allele (P = 0.027). CONCLUSION ATG5 rs473543 genotypes may serve as a potential marker for predicting recurrence of early-stage TNBC patients who received anthracycline-and/or taxane-based regimens as adjuvant chemotherapy.
Adult ; Aged ; Anthracyclines ; administration & dosage ; adverse effects ; Autophagy-Related Protein 5 ; genetics ; Bridged-Ring Compounds ; administration & dosage ; adverse effects ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Neoplasm Recurrence, Local ; drug therapy ; genetics ; pathology ; Polymorphism, Single Nucleotide ; genetics ; Taxoids ; administration & dosage ; adverse effects ; Triple Negative Breast Neoplasms ; drug therapy ; genetics ; pathology

Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTV-PyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumor-infiltrating CD4 T cells and macrophages. An IL-25 neutralization antibody, while not affecting primary tumor growth, substantially reduced lung metastasis. Inhibition of IL-25 resulted in decreased type 2 T cells and macrophages in the primary tumor microenvironments, both reported to enhance breast tumor invasion and subsequent metastasis to the lung. Taken together, our data suggest IL-25 blockade as a novel treatment for metastatic breast tumor.
Animals ; Antibodies, Neoplasm ; pharmacology ; Antibodies, Neutralizing ; pharmacology ; Breast Neoplasms ; drug therapy ; genetics ; immunology ; CD4-Positive T-Lymphocytes ; immunology ; pathology ; Female ; Humans ; Interleukin-17 ; antagonists & inhibitors ; genetics ; immunology ; Interleukins ; antagonists & inhibitors ; genetics ; immunology ; Macrophages ; immunology ; pathology ; Mammary Neoplasms, Animal ; drug therapy ; genetics ; immunology ; Mice ; Neoplasm Metastasis ; Tumor Microenvironment ; drug effects ; genetics ; immunology

The ubiquitin-proteasome system plays a pivotal role in breast tumorigenesis by controlling transcription factors, thus promoting cell cycle growth, and degradation of tumor suppressor proteins. However, breast cancer patients have failed to benefit from proteasome inhibitor treatment partially due to proteasome heterogeneity, which is poorly understood in malignant breast neoplasm. Chemical crosslinking is an increasingly important tool for mapping protein three-dimensional structures and proteinprotein interactions. In the present study, two cross-linkers, bis (sulfosuccinimidyl) suberate (BS(3)) and its water-insoluble analog disuccinimidyl suberate (DSS), were used to map the subunit-subunit interactions in 20S proteasome core particle (CP) from MDA-MB-231 cells. Different types of gel electrophoresis technologies were used. In combination with chemical cross-linking and mass spectrometry, we applied these gel electrophoresis technologies to the study of the noncovalent interactions among 20S proteasome subunits. Firstly, the CP subunit isoforms were profiled. Subsequently, using native/SDSPAGE, it was observed that 0.5 mmol/L BS(3) was a relatively optimal cross-linking concentration for CP subunit-subunit interaction study. 2-DE analysis of the cross-linked CP revealed that α1 might preinteract with α2, and α3 might pre-interact with α4. Moreover, there were different subtypes of α1α2 and α3α4 due to proteasome heterogeneity. There was no significant difference in cross-linking pattern for CP subunits between BS(3) and DSS. Taken together, the gel-based characterization in combination with chemical cross-linking could serve as a tool for the study of subunit interactions within a multi-subunit protein complex. The heterogeneity of 20S proteasome subunit observed in breast cancer cells may provide some key information for proteasome inhibition strategy.
Amino Acid Sequence ; Breast Neoplasms ; drug therapy ; genetics ; pathology ; Cell Line, Tumor ; Cross-Linking Reagents ; administration & dosage ; Electrophoresis, Gel, Two-Dimensional ; Female ; Humans ; Mass Spectrometry ; Proteasome Endopeptidase Complex ; drug effects ; Protein Binding ; drug effects ; Protein Isoforms ; genetics ; Protein Subunits ; biosynthesis ; genetics ; Proteomics ; Succinimides ; administration & dosage

OBJECTIVETo explore the viral etiology of human breast cancer to determine whether there are novel molecular targets for gene therapy of breast cancer and provide evidence for the research of gene therapy and vaccine development for breast cancer.

METHODSPCR was used to screen HPV16 and HPV18 oncogenes E6 and E7 in the SKBR3 cell line and in 76 paraffin embedded breast cancer tissue samples. RNA interference was used to knock down the expression of HPV18 E6 and E7 in SKBR3 cells, then the changes in the expression of cell-cycle related proteins, cell viability, colony formation, metastasis, and cell cycle progression were determined.

RESULTSHPV18 oncogenes E6 and E7 were amplified and sequenced from the SKBR3 cells. Of the patient samples, 6.58% and 23.68% were tested to be positive for HPV18 E6 and HPV18 E7. In the cell culture models, the knockdown of HPV18 E6 and E7 inhibited the proliferation, metastasis, and cell cycle progression of SKBR3 cell. The knockdown also clearly affected the expression levels of cell cycle related proteins.

CONCLUSIONHPV was a contributor to virus caused human breast cancer, suggesting that the oncogenes in HPV were potential targets for gene therapy of breast cancer.

Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Breast Neoplasms ; genetics ; therapy ; Female ; Genetic Therapy ; methods ; Humans ; Middle Aged ; Oncogene Proteins, Viral ; genetics ; metabolism ; Papillomaviridae ; physiology ; Papillomavirus Infections ; genetics ; therapy ; Sequence Alignment

Cytokines are believed to be involved in a "vicious circle" of progressive interactions in bone metastasis. Iguratimod is a novel anti-rheumatic drug which is reported to have the capability of anti-cytokines. In this study, a rat model was constructed to investigate the effect of iguratimod on bone metastasis and it was found that iguratimod alleviated cancer-induced bone destruction. To further explore whether an anti-tumor activity of iguratimod contributes to the effect of bone resorption suppression, two human breast cancer cell lines MDA-MB-231 and MCF-7 were studied. The effect of iguratimod on tumor proliferation was detected by CCK-8 assay and flow cytometry. The effects of iguratimod on migration and invasion of cancer cells were determined by wound-healing and Transwell assays. Results showed that high dose (30 μg/mL) iguratimod slightly suppressed the proliferation of cancer cells but failed to inhibit their migration and invasion capacity. Interestingly, iguratimod decreased the transcription level of IL-6 in MDA-MB-231 cells in a concentration-dependent manner. Moreover, iguratimod partially impaired NF-κB signaling by suppressing the phosphorylation of NF-κB p65 subunit. Our findings indicated that iguratimod may alleviate bone destruction by partially decreasing the expression of IL-6 in an NF-κB-dependent manner, while it has little effect on the tumor proliferation and invasion.
Animals ; Apoptosis ; drug effects ; Bone Neoplasms ; complications ; drug therapy ; pathology ; secondary ; Bone Resorption ; complications ; drug therapy ; pathology ; Breast Neoplasms ; complications ; drug therapy ; genetics ; pathology ; Carcinogenesis ; drug effects ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Chromones ; administration & dosage ; Female ; Humans ; Interleukin-6 ; biosynthesis ; genetics ; MCF-7 Cells ; Neoplasm Invasiveness ; genetics ; pathology ; Rats ; Sulfonamides ; administration & dosage ; Transcription Factor RelA ; biosynthesis ; genetics

The gene types of breast cancer can be classified into three types according to its molecules: Luminal type A, Luminal type B, HER-2-positive type, triple negative type. Authors combined pathological characteristics of breast cancer, biological characteristics, and comprehensive treatment, used syndrome typing based medication, and explored treatment meticulous ideas and methods of "treating the same disease with different methods" as well as "different treatment methods in accordance with patients individually".
Biomarkers, Tumor ; genetics ; Breast Neoplasms ; classification ; genetics ; therapy ; Female ; Humans ; Receptor, ErbB-2 ; genetics