Circular RNAs: novel regulators of resistance to systemic treatments in breast cancer.

Systematic treatments including chemotherapy, endocrine therapy, and HER2-targeted therapy are important therapeutic approaches to breast cancer. However, drug resistance is a major barrier to achieving a cure in breast cancer (BC) patients. Hence, it is urgent to gain insight into the drug-resistance mechanisms in order to improve the prognosis of BC patients. Genetic alternations, epigenetic alternations, and other non-genetic mechanisms such as BC stem-like cells, metabolic reprogramming, and tumor microenvironment contribute to drug resistance of BC. With the development of single-cell sequencing of circulating tumor cell and next-generation sequencing of matched pre- and post- progression tumor biopsies or ctDNA from BC patients with drug resistance, new mechanisms of resistance are being discovered. An increasing number of microRNAs and long non-coding RNAs have been found to be associated with the drug resistance of BC. However, there are few reports on the role of circular RNAs (circRNAs) as master regulators of drug resistance. Therefore, there is still much to say in the field of drug resistance-related circRNAs. In this review, we mainly focus on literature evidence for the detailed mechanisms associated with systematic treatments' resistance of BC and how circRNAs intensify or weaken drug resistance. Exogenous expression of tumor suppressive circRNAs or knockdown of oncogenic circRNAs has been verified to reverse drug resistance of BC cells, which highlights that circRNAs may function as potential biomarkers and/or therapeutic targets of BC. Treatment targeting abnormally expressed circRNAs alone or combined with other systemic treatments may be a promising approach to conquering drug resistance.

The assessment of circulating cell-free DNA as a diagnostic tool for breast cancer: an updated systematic review and meta-analysis of quantitative and qualitative ssays.

OBJECTIVES: This updated meta-analysis aimed to assess the diagnostic accuracy of circulating cell-free DNA (cfDNA) in breast cancer (BC). CONTENT: An extensive systematic search was performed in PubMed, Scopus, Embase, and Science Direct databases to retrieve all related literature. Various diagnostic estimates, including sensitivity (SE), specificity (SP), likelihood ratios (LRs), diagnostic odds ratio (DOR), and area under the curve (AUC) of summary receiver operating characteristic (sROC) curve, were also calculated using bivariate linear mixed models. SUMMARY: In this meta-analysis, 57 unique articles (130 assays) on 4246 BC patients and 2,952 controls, were enrolled. For quantitative approaches, pooled SE, SP, PLR, NLR, DOR, and AUC were obtained as 0.80, 0.88, 6.7, 0.23, 29, and 0.91, respectively. Moreover, for qualitative approaches, pooled SE and SP for diagnostic performance were obtained as 0.36 and 0.98, respectively. In addition, PLR was 14.9 and NLR was 0.66. As well, the combined DOR was 23, and the AUC was 0.79. OUTLOOK: Regardless of promising SE and SP, analysis of LRs suggested that quantitative assays are not robust enough neither for BC confirmation nor for its exclusion. On the other hand, qualitative assays showed satisfying performance only for confirming the diagnosis of BC, but not for its exclusion. Furthermore, qualitative cfDNA assays showed a better diagnostic performance in patients at the advanced stage of cancer, which represented no remarkable clinical significance as a biomarker for early detection.

An evidence-based review of the outcome of fulvestrant plus a targeted agent versus fulvestrant alone in treating hormone receptor-positive endocrine therapy-resistant metastatic breast cancer.

BACKGROUND: Fulvestrant is approved for the hormone receptor-positive advanced metastatic breast cancer (MBC) patients during or after prior endocrine treatment. The adding of a targeted agent to fulvestrant has improved the outlook for these patients from recent studies. However, these results were still under investigation, the analysis was undertaken to assess the clinical outcomes of the fulvestrant-based combination therapy compared with fulvestrant monotherapy. METHODS: I systematically searched electronic databases to identify eligible literatures till January 2019. Randomized-controlled trials (RCTs) assessing the efficacy of a targeted agent to fulvestrant with fulvestrant mono-therapy in MBC patients who are refractory to or intolerant of prior endocrine therapy were included. RESULTS: Six RCTs were included in this analysis. The group of a targeted agent to fulvestrant was significantly improved overall survival (OR = 0.86, 95%CI = 0.76-0.97, P = 0.02), progression-free survival (OR = 0.66, 95%CI = 0.54-0.81, P < 0.0001), as well with the objective response rate (OR = 2.30, 95%CI = 1.67-3.18, P < 0.00001), respectively. However, there are more adverse effects with the combination group (OR = 6.71, 95%CI = 5.58-8.06, P < 0.00001). CONCLUSIONS: Pooled results indicate that adding a targeted agent to fulvestrant prolonged OS, PFS and ORR in relapse or metastatic hormone receptor-positive breast cancer after prior endocrine therapy. Combination of fulvestrant with a targeted agent was associated with more frequent grade 3/4 toxicities. Further research is needed to develop a database of reliable biomarkers and their individual impact on the fulvestrant-based combination treatments.

Hollow MIL-125 Nanoparticles Loading Doxorubicin Prodrug and 3-Methyladenine for Reversal of Tumor Multidrug Resistance.

Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy. Herein, a multifunctional delivery system (HA-MIL-125@DVMA) was prepared for synergistically reverse tumor MDR. Tumor-targeted hollow MIL-125-Ti nanoparticles were used to load the doxorubicin-vitamin E succinate (DV) prodrug and 3-methyladenine (3-MA) to enhance reverse MDR effects. The pH-sensitive DV can kill tumor cells and inhibit P-gp-mediated drug efflux, and 3-MA can inhibit autophagy. HA-MIL-125@DVMA had uniformly distributed particle size and high drug-load content. The nanoparticles could effectively release the drugs into tumor microenvironment due to the rapid hydrazone bond-breaking under low pH conditions, resulting in a high cumulative release rate. In in vitro cellular experiments, the accumulation of HA-MIL-125@DVMA and HA-MIL-125@DV in MCF-7/ADR cells was significantly higher than that in the control groups. Moreover, the nanoparticles significantly inhibited drug efflux in the cells, ensuring the accumulation of the drugs in cell cytoplasm and causing drug-resistant cells' death. Importantly, HA-MIL-125@DVMA effectively inhibited tumor growth without changes in body weight in tumor-bearing mice. In summary, the combination of the acid-sensitive prodrug DV and autophagy inhibitor 3-MA in a HA-MIL-125 nanocarrier can enhance the antitumor effect and reverse tumor MDR.

Berberine Inhibits the Expression of SCT through miR-214-3p Stimulation in Breast Cancer Cells.

In this study, we aimed to evaluate the suppressive abilities of berberine (BBR) on MCF-7 and MDA-MB-231 cells and confirm its underlying mechanisms on miR-214-3p. We first built a panel of 18 miRNAs and 9 lncRNAs that were reported to participate in the mechanism of breast cancer. The RT-qPCR results suggested that BBR illustrated a dosage-dependent pattern in the stimulation to miR-214-3p in both MCF-7 and MDA-MB-231 cells. Then, we performed gain-and-lose function tests to validate the role of miR-214-3p contributing to the anticancer effects of BBR. Both BBR and miR-214-3p mimic reduced the cell viability, repressed migration and invasion capacities, increased rates of total apoptotic cells and ratio of Bax/Bcl-2, and increased the percentage of G2/M cells of MCF-7 and MDA-MB-231 cells by colony formation and CKK8 assay, scratch wound healing and gelatin-based 3D conformation assay, transwell invasion assay, and cell cycle analysis, respectively. However, miR-214-3p inhibitor counteracted all these effects of BBR. Based on the bioinformatics analysis and dual-luciferase reporter test, we identified binding sites between SCT and miR-214-3p. We further confirmed that BBR massively and dose-dependently reduced the mRNA expression and protein levels of SCT in both MCF-7 and MDA-231 cells. We testified that both miR-214-3p mimic and BBR could decrease the mRNA expression and protein levels of SCT, while miR-214-3p inhibitor weakened these reductions. In conclusion, BBR suppressed MCF-7 and MDA-MB-231 breast cancer cells by upregulating miR-214-3p and increasing its inhibition to SCT.

CCAT1: an oncogenic long noncoding RNA in human cancers.

PURPOSE: Long noncoding RNAs (lncRNAs) are a new class of noncoding RNAs that participate in a variety of biological processes such as cell proliferation, cell cycle, differentiation and apoptosis, mainly by regulation of gene expression at various levels, including chromatin, splicing, transcriptional and post-transcriptional levels. CCAT1 is a recently identified oncogenic lncRNA, which has been reported to be consistently upregulated in multiple cancer tissues and closely correlated with initiation and progression of cancers. The aim of this paper is to provide an overview of various roles of CCAT1 in human cancers. METHODS AND RESULTS: We searched studies in electronic databases. Studies have shown the high expression pattern and oncogenic role of CCAT1 in different types of cancer, and aberrant expression of CCAT1 is involved in several processes correlated with carcinogenesis such as cell proliferation, apoptosis, migration and invasion by regulating different target genes and pathways. CONCLUSION: LncRNA CCAT1 promises to be a novel diagnostic biomarker, therapeutic target, as well as prognostic biomarker in human cancers.

[Regional intra-arterial infusion chemotherapy for pancreatic cancer: an experimental study].

OBJECTIVE: To verify the feasibility of regional intra-arterial infusion chemotherapy with gemcitabine for the treatment of locally advanced pancreatic cancer. METHODS: 10 Beagle dogs were divided into two groups: the experimental group and the control group. In the experimental group, gemcitabine (45 mg/kg) were infused via a transfemorally placed catheter into the celiac axis and superior mesenteric artery. IAC was given over 30 min with the help of DSA. In the control group, chemotherapy was performed via peripheral veins with the same dosage as the experimental group. Blood samples, heart, lung, liver, kidney, pancreas and parapancreatic tissues were obtained for drug concentration determination and pathological examination. RESULTS: The serum concentration of experimental group were significantly higher than those of the control group 2 hr, 4 hr and 8 hr after treatment (P < 0.05). Area under curve after dosage-based calibration in experimental group was much higher than that in control group (P < 0.05). The mean retention time of the drug in the animal body was significantly longer in experimental group than in control group. Pancreatic gemcitabine titer in experimental group was significantly higher than that in control group 4 hr and 8 hr after drug administration. There were a large number of red blood cells in the renal glomerulus and tubules, congestion and hemorrahge in the pulmonary capillaries and myocardium in the control group according to pathological examinations. However, infiltration of neutrophilic white blood cells, hemorrahge and fibrinous exudation were present in parapancreatic tissues which were absent in the group. CONCLUSION: Regional intra-arterial infusion chemotherapy with gemcitabine could increase serum and pancreatic drug concentration, prolongs retention time of the drug in the animal body, and is feasible in the treatment of pancreatic cancer.