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Breast cancer is the most common malignant tumor worldwide and the leading cause of cancer-related deaths in female. Metabolic reprogramming plays critical roles in breast tumorigenesis and induces enhanced glucose uptake and glycolysis. TRPC5OS is encoded by short transient receptor potential channel 5 opposite strand, and predicted to correlate with tumor metabolic reprogramming. Here we aim to elucidate the function of TRPC5OS in aberrant metabolism mediated tumorigenesis. We detected TRPC5OS expression levels in cell lines and tissues by quantitative real-time polymerase chain reaction and immunohistochemistry. Then we assessed the effects of TRPC5OS on proliferation and cell cycle progression in breast cancer cells by cell counting kit-8, colony-formation, EdU-incorporation assays and flow cytometry. Tumor growth in vivo was observed in a mouse xenograft model. Mass spectrum analyses were performed to identify potential interactors of TRPC5OS in tumor cells, and the interaction between TRPC5OS and interactors was validated by co-immunoprecipitation (CO-IP), western blots, and immunofluorescent staining. Glucose uptake was measured by liquid scintillation spectrometry. TRPC5OS highly expresses both in breast tumors and cell lines, and might be an independent prognostic marker for breast cancer patients. Overexpressed TRPC5OS promotes breast cancer cell proliferation, cell cycle progression, and enhances tumor xenograft growth. Mass spectral and CO-IP data showed that TRPC5OS interacts with ENO1. We also demonstrate that TRPC5OS could enhance ENO1/PI3K/Akt-mediated glucose uptake in breast cancer cells. Our study demonstrated that TRPC5OS promotes breast tumorigenesis by ENO1/PI3K/Akt-mediated glucose uptake. TRPC5OS might be an independent prognostic marker and potential therapeutic target for breast cancer patients., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The aim of our study was to investigate microRNA (miRNA) expression profiles in CD44 + ovarian cancer stem cells (ovarian CSCs)., Methods: In this study, we enriched CD44 + ovarian CSCs using magnetic activated cell sorting (MACS). A combination of real-time quantitative PCR (qRT-PCR), western blot and sphere formation assays was used to demonstrate stem cell-like properties. RNA sequencing was used to detect the miRNA expression profiles in CD44 + ovarian CSCs. Transient transfection, qRT-PCR, western blot and sphere formation assays were further used to test the function of miR-181a-2-3p., Results: We found that CD44 + ovarian CSCs showed enhanced sphere formation and expression of stemness-associated genes (NANOG, OCT4, SOX2) compared to ovarian cancer cells. The RNA sequencing results showed that the miRNA expression profiles of CD44 + ovarian CSCs were different from those of ovarian cancer cells. GO and KEGG pathway analyses indicated that these miRNAs regulate stem cell-like properties in CD44 + ovarian CSCs. In addition, miR-181a-2-3p negatively regulates the stem cell-like properties of CD44 + ovarian CSCs by targeting EGR1., Conclusion: Our data suggest that miRNAs play important roles in regulating the stem cell-like properties of CD44 + ovarian CSCs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As a key regulator of the DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. Our previous study showed that it plays an essential role in the progression of multiple tumors. However, the mechanism through which RAD18 influences triple-negative breast cancer (TNBC), especially the interaction between tumor cells and the tumor microenvironment, remains elusive. In this study, we showed that RAD18 expression is markedly higher in patients with high T stage TNBC and inversely correlated with prognosis. High expression of RAD18 facilitated a highly stem-cell phenotype through the Hippo/YAP pathway, which supports the proliferation of TNBC. In addition, the cytokine byproduct TGF-β activates macrophages to have an M2-like tumor-associated macrophage (TAM) phenotype. Reciprocally, TGF-β from TAMs activated RAD18 in TNBC to enhance tumor stemness, forming a positive feedback loop. Inhibition of YAP or TGF-β breaks this loop and suppresses cancer stemness and proliferation In nude mice, RAD18 promoted subcutaneous transplanted tumor growth and M2-type TAM recruitment. Collectively, the RAD18-YAP-TGF-β loop is essential for the promotion of the stemness phenotype by TNBC and could be a potential therapeutic target for TNBC., (© 2022. The Author(s).)

Recurrent spontaneous abortion (RSA) is a kind of pathological pregnancy, and abnormal function of trophoblast cells may be related to a variety of pregnancy complications including RSA. Psoralen is an effective ingredient extracted from Cullen corylifolium (L.) Medik. with multiple bioactivities mainly including anti-osteoporotic, anti-tumor, anti-inflammatory, and estrogen-like effects. However, the exact role of psoralen on trophoblast invasiveness has not been investigated thus far. In the present study, the effects of psoralen on the proliferation, migration, and invasion abilities of HTR-8/SVneo cells were evaluated by the CCK-8 and Transwell assays. The expression patterns of nuclear factor κB (NF-κB)/p65 and metalloproteinases (MMP)-2 and MMP-9 were characterized by further experiments including real-time quantitative polymerase chain reaction and Western blot. Indirect immunofluorescence was applied to track the NF-κB p65 translocation. Herein, we found that cell viability and invasive ability were promoted by psoralen in a concentration-dependent manner. Psoralen concentration-dependently enhanced both MMP-2 and MMP-9 expression and their activity of HTR-8/SVneo cells. Additionally, we observed accelerated nuclear accumulation and enhanced nuclear translocation of p65 in the presence of psoralen. Furthermore, invasiveness enhancement of psoralen on HTR-8/SVneo cells was partly eliminated by a NF-κB pathway inhibitor. Thus, our findings suggest that psoralen may serve as a potential repurpose drug candidate that can be used to induce migration and invasion of trophoblast cells through strengthening the NF-κB pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qi, Lu, Fu, Lv and Hou.)

Breast cancer (BC) develops from breast tissue and is the most common aggressive malignant tumor in women worldwide. Although advanced treatment strategies have been applied and reduced current mortality rates, BC control remains unsatisfactory. It is essential to elucidate the underlying molecular mechanisms to assist clinical options. Exosomes are a type of extracellular vesicles and mediate cellular communications by delivering various biomolecules (oncogenes, oncomiRs, proteins, and even pharmacological compounds). These bioactive molecules can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. Extensive studies have implicated exosomes in BC biology, including therapeutic resistance and the surrounding microenvironment. This review focuses on discussing the functions of exosomes in tumor treatment resistance, invasion and metastasis of BC. Moreover, we will also summarize multiple interactions between exosomes and the BC tumor microenvironment. Finally, we propose promising clinical applications of exosomes in BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Sun, Huang, Li, Fu, Li and Yin.)

Breast cancer is the most common cancer worldwide. JWA is a microtubule-associated protein that has been identified as a tumor suppressor, and its downregulation in tumors is an independent adverse prognostic factor. The objective of this study was to explore the expression, regulation, and mechanism of JWA in trastuzumab-resistant breast cancers. In this study, we found that JWA expression was lower in trastuzumab-resistant breast cancers than that in trastuzumab-sensitive breast cancers. Furthermore, it was confirmed that overexpression of JWA inhibited proliferation and promoted apoptosis in trastuzumab-resistant breast cancers both in vitro and in vivo. In addition, the low expression of JWA in trastuzumab-resistant breast cancers is associated with a poor prognosis. Combining RNA-sequence datasets and next-generation sequencing, it was found that JWA negatively regulated CDK12, and was involved in the G1-to-S transition of the cell cycle. It has been reported that CDK12 drives breast cancer initiation and induces trastuzumab resistance. Taken together, high expression of JWA could inhibit the growth of trastuzumab-resistant breast cancer, and JWA is a potential predictive marker for trastuzumab resistance. In addition, targeted therapy with JWA may be a novel therapeutic strategy to improve the survival rate of trastuzumab-resistant breast cancer., (© 2021. The Author(s).)

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors, which are among the most important breakthroughs in precision medicine, have played a crucial role in cancer treatment. Understanding the toxicity profiles of the different PARP inhibitors will improve strategic treatment in clinical practice., Methods: PubMed, Cochrane Library, and Web of Science were systematically searched to include related studies published in English between January 2009 and February 2020. Only prospective, phase II and III randomized controlled trials were included. The following treatment groups were analyzed: niraparib, talazoparib, olaparib, rucaparib, conventional therapy (chemotherapy), one PARP inhibitor with one angiogenesis inhibitor, and placebo. Baseline data and adverse event data were extracted from the Bayesian random-effects network meta-analysis., Results: Fourteen phase II and III randomized controlled trials (4,336 patients) were included. When considering grade 3-5 adverse events, olaparib may be a better choice (probability =57%), followed by conventional therapy (50%), talazoparib (45%), rucaparib (75%), niraparib (77%), and a PARP inhibitor with one angiogenesis inhibitor (94%). Niraparib and rucaparib had higher risks for hematological and gastrointestinal toxicities, respectively. Talazoparib was safer for gastrointestinal function. Constipation and neutropenia were less observed in olaparib, but the risks for anorexia increased. The combination of PARP inhibitor and angiogenesis inhibitor increased the risk of general, metabolic, and gastrointestinal disorders., Conclusions: This network meta-analysis suggested that the toxicity spectrum of each PARP inhibitor is different. Olaparib had the best safety profile among all PARP inhibitors because of its mild toxicity and narrow spectrum. This study may guide clinicians and support further research., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-1883). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Cancer-associated fibroblasts (CAFs) are key components in tumor microenvironment (TME). The secreted products of CAFs play important roles in regulating tumor cells and further impacting clinical prognosis. This study aims to reveal the relationship between CAF-secreted cytokines and breast cancer (BC) by constructing the risk signature. We performed three algorithms to reveal CAF-related cytokines in the TCGA BC dataset and identified five prognosis-related cytokines. Then we used single-cell RNA sequencing (ScRNA-Seq) datasets of BC to confirm the expression level of these five cytokines in CAFs. METABRIC and other independent datasets were utilized to validate the findings in further analyses. Based on the identified five-cytokine signature derived from CAFs, BC patients with high-risk score (RS) had shorter overall survival than low-RS cases. Further analysis suggested that the high-RS level correlated with cell proliferation and mast cell infiltration in BCs of the Basal-like subtype. The results also indicated that the level of RS could discriminate the high-risk BC cases harboring driver mutations (i.e., PI3KCA, CDH1, and TP53). Additionally, the status of five-cytokine signature was associated with the frequency and molecular timing of whole genome duplication (WGD) events. Intratumor heterogeneity (ITH) analysis among BC samples indicated that the high-RS level was associated with the increase of tumor subclones. This work demonstrated that the prognostic signature based on CAF-secreted cytokines was associated with clinical outcome, tumor progression, and genetic alteration. Our findings may provide insights to develop novel strategies for early intervention and prognostic prediction of BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Wang, Zhang, Yang, Zeng, Meng, Yang, Yang, Hua, Fu, Li, Huang, Wu, Yin and Li.)

Breast cancer is one of the most common malignant tumors in women and is the second leading cause of cancer deaths among women. The tumorigenesis and progression of breast cancer are not well understood. The existing researches have indicated that non-coding RNAs, which mainly include long non-coding RNA (lncRNA) and microRNA (miRNA), have gradually become important regulators of breast cancer. We aimed to screen the differential expression of miRNA and lncRNA in the different breast cancer stages and identify the key non-coding RNA using TCGA data. Based on series test of cluster (STC) analysis, bioinformatics analysis, and negatively correlated relationships, 122 lncRNAs, 67 miRNAs, and 119 mRNAs were selected to construct the regulatory network of lncRNA and miRNA. It was shown that the miR-93/20b/106a/106b family was at the center of the regulatory network. Furthermore, 6 miRNAs, 10 lncRNAs, and 15 mRNAs were significantly associated with the overall survival (OS, log-rank P < 0.05) of patients with breast cancer. Overexpressed miR-93 in MCF-7 breast cancer cells was associated with suppressed expression of multiple lncRNAs, and these downregulated lncRNAs (MESTIT1, LOC100128164, and DNMBP-AS1) were significantly associated with poor overall survival in breast cancer patients. Therefore, the miR-93/20b/106a/106b family at the core of the regulatory network discovered by our analysis above may be extremely important for the regulation of lncRNA expression and the progression of breast cancer. The identified key miRNA and lncRNA will enhance the understanding of molecular mechanisms of breast cancer progression. Targeting these key non-coding RNA may provide new therapeutic strategies for breast cancer treatment and may prevent the progression of breast cancer from an early stage to an advanced stage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Lu, Ma, Zhou, Tang, Fu, Wang, Lv and Lu.)

tRNA-derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA-derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA-derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA-derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA-derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA-derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA-derived fragments, the distinct expression and function of tRNA-derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments., (© 2020 UICC.)

Human epidermal growth factor receptor 2 (HER2)-positive is a particularly aggressive type of the breast cancer. Trastuzumab-based therapy is a standard treatment for HER2-positive breast cancer, but some patients are resistant to the therapy. Serum proteins have been used to predict therapeutic benefit for various cancers, but whether serum proteins can serve as biomarkers for HER2-positive breast cancer remains unclear. Using an isobaric Tandem Mass Tag (TMT) label-based quantitative proteomic, we discovered 18 differentially expressed proteins in the serum of trastuzumab-based therapy resistant patients before therapy. Then, four proteins were selected and validated using an LC-MS/MS-based multiple reaction monitoring quantification method, and it was confirmed that three proteins (SRGN, LDHA and CST3) were correlated with trastuzumab-based therapy resistance. Finally, the trastuzumab-based therapy resistance diagnostic score was calculated and acquired by means of a logistic regression pattern based on the level of these three proteins. In summary, we develop a serum-based protein signature that potentially predicts the therapeutic effects of trastuzumab-based therapy for HER2-positive breast cancer patients., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Breast cancer is the leading cause of cancer death in women worldwide. Long non-coding RNA small nucleolar RNA host gene 1 ( SNHG1 ) has been reported to be involved in human diseases, including cancer. Here, we found that SNHG1 expression was significantly upregulated in human breast cancer tissues and cell lines. We explored the function of SNHG1 in breast cancer cells using in vitro and in vivo experiments and found that SNHG1 promotes breast cancer metastasis and proliferation. The potential molecular mechanism of SNHG1 in breast cancer cells may involve SNHG1 acting as a sponge of miR-193a-5p to activate the expression of the oncogene HOXA1 . In summary, our study reveals a novel SNHG1 / miR-193a-5p/HOXA1 competing endogenous RNA regulatory pathway in breast cancer progression and may provide new strategies for breast cancer therapy.

Transfer RNAs (tRNAs) were traditionally considered to participate in protein translation. Recent studies have identified a novel class of small non-coding RNAs (sncRNAs), produced by the specific cleavage of pre- and mature tRNAs, which have been named tRNA-derived fragments. tRNA-derived fragments are classified into diverse subtypes based on the different cleavage positions of the pre- and mature tRNAs. Recently, accumulated evidence has shown that these tRNA-derived fragments are frequently dysregulated in several cancers. Several tRNA-derived fragments were found to participate in cell proliferation, apoptosis, and invasive metastasis in several malignant human tumors. These dysregulated fragments are able to bind both Argonaute proteins and Piwi proteins to regulate gene expression. Some of the newly identified tRNA-derived fragments have been considered as the new biomarkers and therapeutic targets for the treatment of cancer. This review summarizes the biogenesis and biological functions of different subtypes of tRNA-derived fragments and discusses their molecular mechanisms in cancer progression., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although mesoporous materials and magnetic materials are used to enrich glycopeptides, materials sharing both mesoporous structures and magnetic properties have not been reported for glycopeptide analyses. Here we prepared boronic acid-modified magnetic Fe 3 O 4 @mTiO 2 microspheres by covalent binding of boronic acid molecules onto the surfaces of silanized Fe 3 O 4 @mTiO 2 microspheres. The final particles (denoted as B-Fe 3 O 4 @mTiO 2 ) showed a typical magnetic hysteresis curve, indicating superparamagnetic behavior; meanwhile, their mesoporous sizes did not change in spite of the reduction in surface area and pore volume. By using these particles together with conventional poly(methyl methacrylate) (PMMA) nanobeads, we then developed a synergistic approach for highly specific and efficient enrichment of N-glycopeptides/glycoproteins. Owing to the introduction of PMMA nanobeads that have strong adsorption towards nonglycopeptides, the number of N-glycopeptides detected and the signal-to-noise ratio in analyzing standard proteins mixture both increased appreciably. The recovery of N-glycopeptides by the synergistic method reached 92.1%, much improved than from B-Fe 3 O 4 @mTiO 2 alone that was 75.3%. Finally, we tested this approach in the analysis of amniotic fluid, obtaining the maximum number and ratio of N-glycopeptides compared to the use of B-Fe 3 O 4 @mTiO 2 alone and commercial SiMAG-boronic acid particles. This ensemble provides an interesting and efficient enrichment platform for glycoproteomics research.

Heterogeneity is the major obstacle to breast cancer target therapy. Classification of breast cancer with significant biological process may reduce the influence of heterogeneity of intrinsic tumor. We used survival analysis to filter 95 gene sets and classify 638 breast cancer samples into two subtypes based on those gene sets associated with prognosis. Clinical outcome of two subtypes were evaluated with disease-free survival, distant metastasis-free survival, and overall survival levels in three databases and ER+, PR+ HER2+, and TNBC groups. We established a novel classification with 95 prognostic gene sets. In the training and validation cohorts, the subtype 1 was characterized by significant gene sets associated with regulation of metabolic process and enzyme activity and predicted obviously improved clinical outcome than subtype 2, which was enriched by tumor cell division, mitosis, and cell cycle-related gene sets (P < 0.05). When evaluated prognostic impact of subtypes in ER+, PR+ HER2+, and TNBC groups, we found that patients in subtype 1 showed better prognosis in ER+ and PR+ groups (P < 0.05) but had no difference from prognosis of subtype 2 in HER2+ and TNBC groups. These findings may have implications in understanding of breast cancer and filtering effective therapeutic strategies for targeted therapy.

Perfluorooctanoic acid (PFOA) is widely used because of its stain-resistant and water-repellant properties. This study aimed to explore the molecular mechanisms undergoing the stimulation effects of PFOA on cancer cell invasion and matrix metalloproteinases (MMPs) expression. Trans-well filter assay showed that PFOA exposure (≥5 nM) evidently enhanced the invasion ability of the breast cancer cells MDA-MB-231. Luciferase reporter assay, quantitative real-time PCR, western blotting and gelatin zymography consistently demonstrated that mRNA and protein levels of MMP-2/-9 were increased in the cells after PFOA treatment (P<0.05 each). Western blotting revealed that PFOA could activate nuclear factor kappaB (NF-κB) by accelerating NF-κB translocation into the nucleus. Furthermore, addition of NF-κB inhibitor in culture medium could suppress the breast cancer cells invasiveness enhancement and MMP-2/-9 overexpression. This study indicates that PFOA can stimulate breast cancer cells invasion and up-regulate matrix metalloproteinase-2/-9 expression mediated by activating NF-κB, which deserves more environmental health concerns., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. MiR-143 is a well-characterized miRNA involved in adipogenesis and may be involved in regulating insulin resistance. Free fatty acids (FFAs) and adipokines, such as tumor necrosis factor-α (TNF-α), leptin, resistin, and interleukin-6 (IL-6), have already been identified as main regulators of obesity and insulin sensitivity. Therefore, we studied the effects of these inflammatory cytokines on the expression of miR-143. FFAs, resistin, and leptin downregulated miR-143 expression in human adipocytes, whereas TNF-α and IL-6 had little effect on miR-143 expression. These results suggest that the expression of miR-143 is affected by a variety of factors that are related to insulin sensitivity. Therefore, miR-143 may be an important mediator in the development of obesity-related insulin resistance.