PurposeBaicalein, a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. However, little is known about the underlying mechanism in human breast cancer cells. In this study, we examined the apoptotic and autophagic pathways activated following baicalein treatment in human breast cancer cells in vitro and in vivo.Materials and methodsIn in vitro study, we used MTT and clone formation assay to confirm the inhibitory role of baicalein on proliferation of MCF-7 and MDA-MB-231 breast cancer cells. Apoptosis was detected employing Hoechst 33258 staining, JC-1 staining, and flow cytometry. Autophagy was monitored by acridine orange staining and transmission electron microscopy observation. Quantitative real-time PCR and Western blot analysis were employed to study the effects of baicalein on PI3K/AKT signaling components of MCF-7 and MDA-MB-231 breast cancer cells. In in vivo study, the effect of baicalein was tested with a breast cancer cells transplantation tumor model.ResultsOur study showed that baicalein has the potential to suppress cell proliferation, induce apoptosis and autophagy of breast cancer cells in vitro and in vivo. Furthermore, baicalein significantly downregulated the expression of p-AKT, p-mTOR, NF-κB, and p-IκB while enhancing the expression of IκB in MCF-7 and MDA-MB-231 cells. It also decreased the p-AKT/AKT and p-mTOR/mTOR ratios.ConclusionOur study demonstrated that baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting the PI3K/AKT signaling pathway in vivo and vitro. Our study revealed that baicalein may be a potential therapeutic agent for breast cancer.

BackgroundThe flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms.MethodsMTT assay was used to examine the inhibition of baicalein on proliferation of MDA-MB-231 cells. Wound healing assay and the in vitro invasion assay was carried out to investigate the effects of baicalein on migration and invasion of MDA-MB-231 cells, respectively. In order to explore the effects of baicalein on tumor metastasis in vivo, xenograft nude mouse model of MDA-MB-231 cells was established. Animals were randomly divided into four groups (control, therapy group, and low-dose and high-dose prevention group, n=6), and treated with baicalein as designed. Following sacrifice, their lungs and livers were collected to examine the presence of metastases. qRT-PCR and Western blot were performed to study the effects of baicalein on expression of SATB1, EMT-related molecules, and Wnt/β-catenin signaling components of MDA-MB-231 cells as well as the metastatic tissue. Effects of baicalein on the expression of target proteins in vivo were also analyzed by immunohistochemistry.ResultsOur results indicated that baicalein suppressed proliferation, migration, and invasion of MDA-MB-231 cells in a time- and dose-dependent manner. Based on assays carried out in xenograft nude mouse model, we found that baicalein inhibited tumor metastasis in vivo. Furthermore, baicalein significantly decreased the expression of SATB1 in MDA-MB-231 cells. It suppressed the expression of vimentin and SNAIL while enhancing the expression of E-cadherin. Baicalein also downregulated the expression of Wnt1 and β-catenin proteins and transcription level of Wnt/β-catenin-targeted genes.ConclusionOur results demonstrate that baicalein has the potential to suppress breast cancer metastasis, possibly by inhibition of EMT, which may be attributed to downregulation of both SATB1 and the Wnt/β-catenin pathway. Taken together, baicalein may serve as a promising drug for metastasis treatment of breast cancer.

Three functional microRNA polymorphisms (miR-499 rs3746444 A > G, miR-196a rs11614913 C > T and miR-146a rs2910164 G > C) have been reported to be associated with breast cancer (BC) risk. However, the results of the published studies are inconsistent. In order to obtain a more credible result, we conducted this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association. Thirty-eight eligible studies with 17,417 cases and 18,988 controls were included in this meta-analysis. Our results showed that the rs3746444 was associated with an increased breast cancer risk in the four genetic models (G vs. A: OR = 1.17, P = 0.008; GG vs. AA: OR = 1.41, P < 0.001; AG vs. AA: OR = 1.10, P = 0.036; GG+AG vs. AA: OR = 1.16, P = 0.001). In the subgroup analysis by ethnicity, significant correlation remained in Asians but not in Caucasians. For rs11614913, obvious decreased breast cancer risk was observed in Caucasian populations (T vs. C: OR = 0.93, P = 0.044). However, we couldn't detect an association between rs2910164 and breast cancer risk. This meta-analysis demonstrates that rs3746444 could increase breast cancer risk in Asians and in general populations, while rs11614913 could decrease the risk of breast cancer in Caucasians. The rs2910164 polymorphism has no association with breast cancer risk. More multicenter studies with larger sample sizes are required to verify our results.

BackgroundMicroRNAs (miRNAs) are small non-coding RNA molecules, which participate in diverse biological processes and may regulate tumor suppressor genes or oncogenes. Rs11614913 in miR-196a2 and rs3746444 in miR-499 are shown to associate with increased/decreased cancer risk. This meta-analysis was performed to systematically assess the overall association.Materials and MethodsWe searched Pubmed, Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until December 2016 to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations.ResultsWe assessed published studies of the association between these microRNA polymorphisms and cancer risk from 56 studies with 21958/26436 cases/controls for miR-196a2 and from 37 studies with 13759/17946 cases/controls for miR-499. The results demonstrated that miR-196a2 rs11614913 was significantly associated with a decreased cancer risk, in particular with a decreased risk for colorectal cancer and gastric cancer, or for Asian population subgroup. In addition, miR-499 rs3746444 polymorphism was observed as a risk factor for cancers, in particular, for breast cancer, or for in the Asian population.ConclusionsOur meta-analysis suggests that the rs11614913 most likely contributes to decreased susceptibility to cancer, especially in Asians and colorectal cancer and gastric cancer, and that the rs3746444 may increase risk for cancer. Furthermore, more well-designed studies with large sample size are still necessary to further elucidate the association between polymorphisms and different kinds of cancers risk.

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Many studies have been conducted to investigate the association between miR-27 rs895819 A > G and miR-423 rs6505162 C > A and cancer risk; however, the results are not consistent. In order to acquire a more precise assessment of the correlation, we performed this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of these two microRNA polymorphisms with cancer risk. Forty-five eligible studies from thirty-five articles were included in our analysis. The results showed that rs895819 was associated with a decreased cancer risk in Caucasians (AG vs. AA: OR = 0.87, 95% CI = 0.79-0.96; GG+AG vs. AA: OR = 0.89, 95% CI = 0.81-0.98). When grouped by ethnicity, an increased risk was observed in colorectal cancer (G vs. A: OR = 1.19, 95% CI = 1.08-1.32; GG vs. AA: OR = 1.58, 95% CI = 1.28-1.96; GG vs. AG+AA: OR = 1.58, 95% CI = 1.29-1.93), while a decreased risk was found in breast cancer (G vs. A: OR = 0.93, 95% CI = 0.87-0.99; GG+AG vs. AA: OR = 0.91, 95% CI = 0.83-0.99). For rs6505162, a significantly decreased cancer risk was observed in lung cancer under all five genetic models. To summarize, our results indicated that rs895819 was a protective factor for cancer in Caucasians and could increase colorectal cancer risk but decrease breast cancer risk. Moreover, rs6505162 was a protective factor for lung cancer.

Abstract. Breast cancer is one of the most commonly occurring female malignant tumors. According to the 2012 GLOBOCAN statistics, produced by the International Agency for Research On Cancer (ʻIARCʼ), nearly 1.7 million women were diagnosed with breast cancer, with 522,000 related deaths: An increase in the incidence of breast cancer and associated mortality by nearly 18% from 2008. Metastasis is the final step in breast cancer progression, and represents the most common cause of mortality in patients with breast cancer. Therefore, a search for low-toxicity, safe and effective anti-breast cancer drugs in the form of natural compounds has become an intense focus of research. Baicalein, a widely used Chinese herbal medicine, has extensive antitumor activity. The present review briefly describes the research that has been performed on the association between baicalein and breast cancer metastasis, and further illustrates the influence of baicalein on the underlying mechanisms of breast cancer metastasis, adding a novel theory basis for baicalein antitumor research. In conclusion, baicalein may represent a promising target for the prevention and therapy of breast cancer.

BackgroundBreast cancer is the most common cancer worldwide. Hypoxia and lactate metabolism are hallmarks of cancer. This study aimed to construct a novel hypoxia- and lactate metabolism-related gene signature to predict the survival, immune microenvironment, and treatment response of breast cancer patients.MethodsRNA-seq and clinical data of breast cancer from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Hypoxia- and lactate metabolism-related genes were collected from publicly available data sources. The differentially expressed genes were identified using the “edgeR” R package. Univariate Cox regression, random survival forest (RSF), and stepwise multivariate Cox regression analyses were performed to construct the hypoxia-lactate metabolism-related prognostic model (HLMRPM). Further analyses, including functional enrichment, ESTIMATE, CIBERSORTx, Immune Cell Abundance Identifier (ImmuCellAI), TIDE, immunophenoscore (IPS), pRRophetic, and CellMiner, were performed to analyze immune status and treatment responses.ResultsWe identified 181 differentially expressed hypoxia-lactate metabolism-related genes (HLMRGs), 24 of which were valuable prognostic genes. Using RSF and stepwise multivariate Cox regression analysis, five HLMRGs were included to establish the HLMRPM. According to the medium-risk score, patients were divided into high- and low-risk groups. Patients in the high-risk group had a worse prognosis than those in the low-risk group (P &lt; 0.05). A nomogram was further built to predict overall survival (OS). Functional enrichment analyses showed that the low-risk group was enriched with immune-related pathways, such as antigen processing and presentation and cytokine-cytokine receptor interaction, whereas the high-risk group was enriched in mTOR and Wnt signaling pathways. CIBERSORTx and ImmuCellAI showed that the low-risk group had abundant anti-tumor immune cells, whereas in the high-risk group, immunosuppressive cells were dominant. Independent immunotherapy datasets (IMvigor210 and GSE78220), TIDE, IPS and pRRophetic analyses revealed that the low-risk group responded better to common immunotherapy and chemotherapy drugs.ConclusionsWe constructed a novel prognostic signature combining lactate metabolism and hypoxia to predict OS, immune status, and treatment response of patients with breast cancer, providing a viewpoint for individualized treatment.