The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment.

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.

Novel disulfidptosis-derived gene blueprint stratifying patients with breast cancer.

INTRODUCTION: Breast cancer remains the predominant cancer among females, accounting for about 24.2% of all cancer cases. Alarmingly, it is the primary cause of cancer-related mortality in women under 45. METHODS: This research analyzed RNA sequencing data from 1082 TCGA-BRCA and 107 GSE58812 breast cancer patients. Single-cell RNA data from five patients in the GSE118389 data set were also studied. Using Random forest and COX regression, we developed a prognostic model. Pathway analysis employed GSVA and GO, while immune profiles were assessed via ssGSEA and MCPcounter. Mutation patterns utilized maftools, and drug sensitivity scores were derived from the GDSC database with oncoPredict. RESULTS: Analysis of the GSE118389 data set identified three distinct cell types: immune, epithelial, and stromal. P53 and VEGF were notably enriched. Five key genes (TMEM251, ADAMTSL2, CDC123, PSMD1, TLE1) were pinpointed for their prognostic significance. We introduced a disulfidptosis-associated score as a novel risk factor for breast cancer prognosis. Survival outcomes varied significantly between training and validation sets. Comprehensive immune profiling revealed no difference in activated CD8-positive T cells between risk groups, but a positive correlation of NK cells, neutrophils, cytotoxic lymphocytes, and monocytic cells with the riskscore was noted. Importantly, a negative association between the drug Nelarabine and riskscore was identified. CONCLUSION: This research underscores the significance of a disulfidptosis-associated gene signature in breast cancer prognosis.

Assessing regional employment effects of the national emission trading scheme in China: Does Okun's law work?

Employment creation and climate change mitigation are core tasks for achieving sustainable development goals. Whether or not carbon mitigation policy facilitate employment deserves deep exploration. Through the construction of multi-regional dynamic computable general equilibrium model (CGE) with more scientific energy & environment block, this paper first evaluates regional employment effects of the national emission trading scheme (ETS) in China. Furthermore, we explore the Okun's law of the national ETS based on the mediating effect model. The results show that whether in carbon-intensive industries (CIIs) or non-carbon-intensive industries (NCIIs), employment effects of the national ETS are differentiated across regions. Specifically, the national ETS generally promotes CIIs' employment in Southern, Eastern, Middle Yangtze River and Southwest regions, and has negative effects on CIIs' employment in other regions. Meanwhile, the national ETS brings employment creation to NCIIs of Southern region, while there are opposite results in NCIIs of Northeast region and mixed results in NCIIs of other regions. Moreover, the Okun's law of the national ETS holds in CIIs of each region, but it not fits the data for NCIIs. Therefore, it is important for the Chinese government to consider the differentiated employment effects in different regions carefully rather than adopt one-size-fit-all solution when constructing the national carbon market.

Apolipoprotein C1 (APOC1), A Candidate Diagnostic Serum Biomarker for Breast Cancer Identified by Serum Proteomics Study.

Purpose - The present study aimed to identify differently expressed peptides involved in BC as potential biomarkers. Experimental Design - The serum proteomic profiling of 128 serum samples from 64 BC patients and 64 healthy controls (HC), using magnetic beads based immobilized metal ion affinity chromatography (MB-IMAC-Cu) separation followed by MALDI-TOF MS. ClinProTools software identified a number of distinct markers. Then, we performed liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) to identify the candidate serum biomarker based on serum proteomics analysis. Finally, enzyme-linked immunosorbent assays (ELISAs) were used to verify the expression of the candidate serum biomarker in BC patients. Results - BC patients could be identified with sensitivity of 87.32% and specificity of 89.46%. Of 41 m/z peaks that differed between BC and HC, six peaks were significantly different between BC and HC (P < 0.01, fold change > 1.5), with peak 1 upregulated and peaks 2-6 downregulated in the BC group. The upregulated peak 1 (m/z: 6638.63) is identified as a region of apolipoprotein C1 (APOC1), and validation showed that APOC1 expression increased from healthy controls to those with FA as well as mastopathy, and finally BC patients. Conclusions and Clinical Relevance - The present study indicates that APOC1 could serve as a candidate serum diagnostic biomarker for BC.

Chemical approaches for the preparation of ubiquitinated proteins via natural linkages.

Ubiquitination is an important posttranslation modification (PTM) that regulates a variety of cellular processes, including protein degradation, DNA repair, and viral infections. In this process, the C-terminal carboxyl group of ubiquitin (Ub) or poly-Ub is attached to the ε-amine of lysine (Lys) side chain of an acceptor protein through an isopeptide bond. Studying a molecular mechanism of ubiquitination and deubiquitination is fundamental for unraveling its precise role in health and disease and hence crucial for drug development. Enzymatic approaches for protein ubiquitination possess limited ability to selectivity install Ub or Ub chain on the desired position of an acceptor protein and often lead to heterogeneous mixtures. In the past decades, chemical protein (semi)synthesis has been proved to be an efficient tool to facilitate site-specific protein ubiquitination, which significantly contributes to decode the Ub signal at molecular and structural levels. In this review, we summarize the synthetic strategies developed for protein ubiquitination, and the achievements to generate monoubiquitinated, di-ubiquitinated, and tetraubiquitinated proteins with native isopeptide and ester bonds.

SIRT1-mediated deacetylation of NF-κB inhibits the MLCK/MLC2 pathway and the expression of ET-1, thus alleviating the development of coronary artery spasm.

Coronary artery spasm (CAS) is an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion. The cardioprotective effect of sirtuin-1 (SIRT1) has been extensively highlighted in coronary artery diseases. The aims within this study include the investigation of the molecular mechanism by which SIRT1 alleviates CAS. SIRT1 expression was first determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis in an endothelin-1 (ET-1)-induced rat CAS model. Interaction among SIRT1, nuclear factor-kappaB (NF-κB), myosin light chain kinase/myosin light chain-2 (MLCK/MLC2), and ET-1 was analyzed using luciferase reporter assay, RT-qPCR, and Western blot analysis. After ectopic expression and depletion experiments in vascular smooth muscle cells (VSMCs), contraction and proliferation of VSMCs and expression of contraction-related proteins (α-SMA, calponin, and SM22α) were measured by collagen gel contraction, 5-ethynyl-2'-deoxyuridine (EdU) assay, RT-qPCR, and Western blot analysis. The obtained results showed that SIRT1 expression was reduced in rat CAS models. However, overexpression of SIRT1 inhibited the contraction and proliferation of VSMCs in vitro. Mechanistic investigation indicated that SIRT1 inhibited NF-κB expression through deacetylation. Moreover, NF-κB could activate the MLCK/MLC2 pathway and upregulate ET-1 expression by binding to their promoter regions, thus inducing VSMC contraction and proliferation in vitro. In vivo experimental results also revealed that SIRT1 alleviated CAS through regulation of the NF-κB/MLCK/MLC2/ET-1 signaling axis. Collectively, our data suggested that SIRT1 could mediate the deacetylation of NF-κB, disrupt the MLCK/MLC2 pathway, and inhibit the expression of ET-1 to relieve CAS, providing a theoretical basis for the prospect of CAS treatment and prevention.NEW & NOTEWORTHY Rat coronary artery spasm models exhibit reduced expression of SIRT1. Overexpression of SIRT1 inhibits contraction and proliferation of VSMCs. SIRT1 inhibits NF-κB through deacetylation to modulate VSMC contraction and proliferation. NF-κB activates the MLCK/MLC2 pathway. NF-κB upregulates ET-1 to modulate VSMC contraction and proliferation.

The association between alcohol consumption and osteoarthritis: a meta-analysis and meta-regression of observational studies.

There is conflicting evidence for the association between alcohol consumption and common joint conditions such as Osteoarthritis (OA), which affects millions of people. We sought to determine the true association between alcohol intake and OA. We conducted a PRISMA systematic review and meta-analysis of observational studies that reported associations between alcohol consumption and OA. Pooled estimates of association were represented through odds ratios (ORs). Publication bias was assessed with Funnel and Galbraith plots, and risk of bias was assessed with the Newcastle Ottawa Scale. We included 29 studies and 25,192 subjects with OA and reported an OR between any alcohol consumption and OA of 0.79 (0.68-0.93), suggesting a protective effect. OR of weekly or more frequent use was 0.79 (0.65-0.97). When grouped by covariates, alcohol consumption was negatively associated with radiographic (0.83, 0.70-0.98), hand (0.80, 0.66-0.95) and knee OA (0.85, 0.72-0.99), North American ethnicity and female gender. Subgroup analysis of unadjusted data resulted in an OR of 0.70 (0.55-0.89) but this disappeared upon analysis of studies with data adjusted for any covariate (0.93, 0.78-1.10). Whilst our pooled analysis suggest that weekly or more frequent alcohol consumption was negatively associated with OA, this was not observed when adjusted for confounding factors. Reasons for this include selection bias and lack of longitudinal exposure and adjustment for confounding variables. Therefore, this meta-analysis provides evidence to dispel notions that alcohol use may be protective against OA.

[Research on regularity of traditional Chinese medicine in treatment of Alzheimer's disease based on data mining].

To explore prescription medication regularity in the treatment of Alzheimer's disease with traditional Chinese medicine(TCM). With Alzheimer's disease or senile dementia as the subject, collecting and sorting out the journal papers in CNKI were collected as the data source to establish the literature research database of Alzheimer's disease prescriptions, and then the association rule analysis, factor analysis and systematic cluster analysis on the included TCM were conducted. Among the 113 prescriptions included in the standard, the single herb Acori Tatarinowii Rhizoma was the most common. The herbs were mainly warm and flat among four pro-perties, mainly sweet, bitter and spicy among five flavors. The drugs were mainly distributed in five internal organs, and the most commonly used drugs were deficiency tonifying drugs as well as blood activating and stasis removing drugs. In the association rule analysis, it was found that there were 6 drug pairs with the highest association strength. Eight common factors were extracted from the factor analysis, and they were classified into 6 categories in the systematic cluster analysis. The results have shown that the overall principles in treating Alzheimer's disease with modern Chinese medicine are tonifying deficiency, invigorating circulation, activating blood and dispelling phlegm.

Ectodermal-neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt/ß-catenin pathway.

Breast cancer, as the most common malignancy, is the second leading cause of cancer-related death in women. One of the kelch family member ENC1 is involved in various pathophysiologic processes. But the role of ENC1 in breast cancer has not been investigated. The present study value the feature, clinical significance and the molecular mechanisms of ENC1 in breast cancer. The expression and prognosis value of ENC1 expression among breast cancer and normal breast tissue were investigated in The Cancer Genome Atlas database and human samples. ENC1 was knockdown to explore its function in various breast cancer cell lines. Western blot was performed to explore the potential molecular mechanisms. We observed that ENC1 was overexpressed in breast cancer tissues. ENC1 overexpression was associated with high metastasis and predicted a poor prognosis in patients with breast cancer. ENC1 Knockdown inhibits the growth, clone formation, migration and invasion of breast cancer cells. Mechanism analysis revealed ENC1 was strong associated with the metastasis by modulating ß-catenin pathway. Our study emphasizes that ENC1 is a potential prognostic and metastasis-related marker of breast cancer, and may function as a possible therapeutic target against breast cancer.

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple-negative breast cancer.

As an aggressive breast cancer (BCa) subtype, triple-negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver-specific bHLH-Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first-line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor-ß1 (TGF-ß1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF-ß1 in a time- and dose-dependent manner. Collectively, these findings suggest that LISCH7 and TGF-ß1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF-ß1 signaling may represent a more effective approach to counteract advanced TNBC.

Downregulation of microRNA-135b promotes atherosclerotic plaque stabilization in atherosclerotic mice by upregulating erythropoietin receptor.

Atherosclerotic plaque rupture is an important pathophysiologic mechanism of acute coronary syndrome. Emerging microRNAs (miRNAs) have been implicated in the atherosclerotic plaque formation and macrophage autophagy during the development of atherosclerosis (AS). Hence, this study was conducted to explore the role microRNA-135b (miR-135b) in macrophages and atherosclerotic plaque in mouse models of AS. The expression of miR-135b and erythropoietin receptor (EPOR) was altered in atherosclerotic mice to clarify their effect on inflammation, cell activities of aortic tissues, and macrophage autophagy. The obtained findings unraveled that miR-135b was upregulated and EPOR was downregulated in atherosclerotic mice. Upregulated miR-135b expression promoted cell apoptosis and inflammation, along with inhibited cell proliferation and decreased macrophage autophagy. Notably, miR-135 was validated to target EPOR and activate the PI3K/Akt signaling pathway. Moreover, miR-135b inhibition attenuated inflammation, atherosclerotic plaque development, and promoted macrophage autophagy. Besides, the effect of miR-135b inhibition was reversed in response to EPOR silencing. Taken conjointly, the study revealed that inhibition of miR-135b promoted macrophage autophagy and atherosclerotic plaque stabilization in atherosclerotic mice by inactivating the PI3K/Akt signaling pathway and upregulating EPOR.

Detection of Moving Load on Pavement Using Piezoelectric Sensors.

More and more researches have been carried out recently on Weigh-In-Motion (WIM) technology for solving the traffic safety problems caused by overload. In this article, we aim to study the measurement accuracy of the WIM system. Based on the electromechanical theory and elastic half-space method, we establish a theoretical model of multi-layer structure to investigate the correlation between the output voltage of the piezoelectric sensor and the applied force. In addition, we performed cyclic and moving load experiments to verify the accuracy of the analytical calculations. The load magnitude identified by this theoretical model matched the experiments very well, which shows that this model is effective for the WIM system. In addition, we proved that the load frequency is an important factor affecting the measurement accuracy of the sensor, which further enables us to design more suitable sensors for certain use scenarios.

Effects of velvet antler polypeptides on Alzheimer's disease cell model via miR-613 HDAC6 pathway.

To study the effect of velvet antler polypeptides (VAP) on Alzheimer's disease (AD) cell model, Aß25-35 was used to induce SK-N-SH cells to obtain AD cell model. The MDA, SOD, GSH-Px levels were determined using relevant kits. Flow cytometry was conducted to detect apoptosis, Western blot was employed to measure Bcl-2, Bax, HDAC6 protein expression, and qPCR was used to assay microRNA (miR)-613 and HDAC6 mRNA levels. Target Scan prediction combined with dual luciferase reporting experiments was conducted to analyze the targeting relationship between miR-613 and HDAC6. miR-613 was transfected in SK-N-SH cells; Alternatively, anti-miR-613 was transfected, followed by Aß25-35 and 80 mg/L of VAP. The AD model cells showed increased MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but lower SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). VAP reduced MDA content, apoptosis rate, Bax protein expression, HDAC6 mRNA and protein expression, but enhanced SOD, GSH-Px activities, Bcl-2 protein level, and miR-613 expression (p<0.05). Over-expression of miR-613 increased SOD, GSH-Px activities, and Bcl-2 protein expression in AD model cells, but reduced HDAC6 protein levels, MDA content, apoptosis rate, and Bax protein levels (p<0.05). VAP may regulate Aß25-35-induced apoptosis so as to treat Alzheimer's disease.

Disodium Salts of Pseudoephedrine-Derived Myers Enolates: Stereoselectivity and Mechanism of Alkylation.

Pseudoephedrine-derived dianionic Myers enolates were generated using sodium diisopropylamide (NaDA) in THF solution. The reactivities and selectivities of the disodium salts largely mirror those of the dilithium salts but without the requisite large excesses of inorganic salts (LiCl) or mandated dilute solutions. The disodium salts require careful control of temperature to preclude deleterious aggregate aging effects traced to changes in the aggregate structure and intervening O-alkylations. Structural studies and density functional theory (DFT) computations show a dominant highly symmetric polyhedron quite different from the lithium analogue. No enolate-NaDA mixed aggregates are observed with excess NaDA. Rate studies show an alkylation mechanism involving an intervening tetramer-monomer pre-equilibrium followed by rate-limiting alkylation of tetrasolvated monomers. DFT computations were conducted to explore the possible influences on stereochemistry. A crystal deriving from samples aged at ambient temperature contains six dianionic subunits and two monoanionic (alkoxide-only) subunits. A new preparation of concentrated solutions of NaDA in THF solution is described.

Pseudophedrine-Derived Myers Enolates: Structures and Influence of Lithium Chloride on Reactivity and Mechanism.

The structures and reactivities of pseudoephedrine-derived dianionic Myers enolates are examined. A combination of NMR and IR spectroscopic, crystallographic, and computational data reveal that the homoaggregated dianions form octalithiated tetramers displaying S4-symmetric Li8O8 cores and overall C2 symmetry. Computational and isotopic labeling studies reveal strong N-Li contacts in the carboxamide enolate moiety. The method of continuous variations proves deceptive, as octalithiated tetrameric homoaggregates afford hexalithiated trimeric heteroaggregates. A lithium diisopropylamide-lithium enolate mixed aggregate is found to be a C2-symmetric hexalithiated species incorporating two enolate dianions and two lithium diisopropylamide (LDA) subunits. Structural and rate studies show that lithium chloride has little effect on the dynamics of the enolate homoaggregates but forms adducts of unknown structure. Rate studies of alkylations indicate that the aging of the aggregates can have effects spanning orders of magnitude. The LiCl-enolate adduct dramatically accelerates the reaction but requires superstoichiometric quantities owing to putative autoinhibition. Efforts and progress toward eliminating the requisite large excess of LiCl are discussed.

Prognostic Value of Lymphovascular Invasion in Patients with Stage III Colorectal Cancer: A Retrospective Study.

BACKGROUND Lymph node metastasis and tumor progression depend on lymphovascular invasion (LVI). This study aimed to investigate the prognostic role of LVI in patients with stage III colorectal cancer (CRC) and to develop a prognostic nomogram. MATERIAL AND METHODS A retrospective study included 437 patients with stage III CRC. The impact of LVI on overall survival (OS) was analyzed with the Kaplan-Meier method and Cox regression model. A nomogram was constructed, and its predictive accuracy was evaluated using the concordance index (C-index) and the calibration plot. RESULTS LVI was found in 19.7% of cases of stage III CRCs and was significantly correlated with high tumor grade (poor differentiation) and advanced tumor stage (all P<0.05). Patients age, a family history of cancer in a first-degree relative, pre-treatment levels of carcinoembryonic antigen (CEA), prognostic nutritional index (PNI), histological tumor grade, tumor-node-metastasis (TNM) stage, and LVI were independent prognostic indicators (all P<0.05). Compared with the LVI(-) group, patients in the LVI(+) group showed a 1.748-fold increased risk of death (P=0.004) and a significantly reduced OS rate (P<0.001). In the prognostic nomogram, the C-index was significantly increased with LVI compared with the TNM stage alone (0.742 vs. 0.593; P<0.001). Calibration plots showed good fitness of the nomogram for prediction of survival. Comparison of the nomograms with and without LVI showed that inclusion of LVI improved the C-index from 0.715 to 0.742. CONCLUSIONS LVI was an indicator of more aggressive biological behavior and poor prognosis in patients with stage III CRC.

Activation of the IL-6/JAK2/STAT3 pathway induces plasma cell mastitis in mice.

Plasma cell mastitis (PCM) is a chronic mastitis with limited treatment options and common recurrence. A histopathological hallmark of PCM is the infiltration of numerous plasma cells surrounding the mammary duct. Our previous study showed that the activity of the IL-6/STAT3 signaling pathway was elevated in patients with PCM. However, the etiology of PCM remains largely unclear. In this study, we sought to explore the effects of IL-6/JAK2/STAT3 signaling pathway in the pathogenesis of PCM. Histological analysis showed that the mammary glands of mice that received human breast tissue homogenates, followed by an injection of IL-6, exhibited features of PCM similar to human PCM. The IL-6/JAK2/STAT3 signaling activity was significantly elevated and Bcl-2 was highly expressed in CD138 + plasma cells in the mammary glands of mice with PCM. Furthermore, treatment with AG-490, an inhibitor of JAK family kinases, suppressed activation of the IL-6/JAK2/STAT3 signaling cascade, in turn resulting in a decreased number of plasma cells in the mammary gland and reversing the pathogenesis of PCM. Taken together, our study indicated that a PCM mouse model was successfully established through activation of the IL-6/JAK2/STAT3 pathway by injecting IL-6 into the mammary gland of mouse that had received homogenates of human breast tissue. Thus, the IL-6/JAK2/STAT3 signaling pathway plays a critical role in orchestrating the pathogenesis of PCM.

Railway Tunnel Clearance Inspection Method Based on 3D Point Cloud from Mobile Laser Scanning.

Railway tunnel clearance is directly related to the safe operation of trains and upgrading of freight capacity. As more and more railway are put into operation and the operation is continuously becoming faster, the railway tunnel clearance inspection should be more precise and efficient. In view of the problems existing in traditional tunnel clearance inspection methods, such as low density, slow speed and a lot of manual operations, this paper proposes a tunnel clearance inspection approach based on 3D point clouds obtained by a mobile laser scanning system (MLS). First, a dynamic coordinate system for railway tunnel clearance inspection has been proposed. A rail line extraction algorithm based on 3D linear fitting is implemented from the segmented point cloud to establish a dynamic clearance coordinate system. Second, a method to seamlessly connect all rail segments based on the railway clearance restrictions, and a seamless rail alignment is formed sequentially from the middle tunnel section to both ends. Finally, based on the rail alignment and the track clearance coordinate system, different types of clearance frames are introduced for intrusion operation with the tunnel section to realize the tunnel clearance inspection. By taking the Shuanghekou Tunnel of the Chengdu-Kunming Railway as an example, when the clearance inspection is carried out by the method mentioned herein, its precision can reach 0.03 m, and difference types of clearances can be effectively calculated. This method has a wide application prospects.

Tumor-suppressive microRNA-34a inhibits breast cancer cell migration and invasion via targeting oncogenic TPD52.

The tumor protein D52 (TPD52) is an oncogene overexpressed in breast cancer. Although the oncogenic effects of TPD52 are well recognized, how its expression and the role in migration/invasion is still not clear. This study tried to explore the regulative role of microRNA-34a (miR-34a), a tumor suppressive miRNA, on TPD52 expression in breast cancer. The expression of miR-34a was found significantly decreased in breast cancer specimens with lymph node metastases and breast cancer cell lines. The clinicopathological characteristics analyzed showed that lower expression levels of miR-34a were associated with advanced clinical stages. Moreover, TPD52 was demonstrated as one of miR-34a direct targets in human breast cancer cells. miR-34a was further found significantly repress epithelial-mesenchymal transition (EMT) and inhibit breast cancer cell migration and invasion via TPD52. These findings indicate that miR-34a inhibits breast cancer progression and metastasis through targeting TPD52. Consequently, our data strongly suggested that oncogenic TPD52 pathway regulated by miR-34a might be useful to reveal new therapeutic targets for breast cancer.

Enhanced SLC34A2 in breast cancer stem cell-like cells induces chemotherapeutic resistance to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling.

Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44(+)CD24(-) cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44(+)CD24(-) cells from spheres, we showed that CD44(+)CD24(-) cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments. Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer.