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Background: The survival outcomes in HER2-low versus HER2-zero breast cancer (BC) after neoadjuvant chemotherapy (NACT) remain unclear. The meta-analysis was conducted to summarize current evidence about the survival outcomes in HER2-low versus HER2-zero BC. Methods: We conducted a systematic search in PubMed and EMBASE databases to identify relevant studies. Results: A total of 14 studies with 53,714 patients were included. Overall, 34,037 patients (63.37%) were HER2-low, and 19,677 patients (36.63%) were HER2-zero. Patients with HER2-low tumors had a significantly lower pathological complete response (pCR) rate than patients with HER2-zero tumors, regardless of the hormone receptor status. Compared with HER2-zero breast cancer, the overall survival (OS) and disease-free survival (DFS) of HER2-low BC were longer in the overall cohort (HR = 0.72; 95% CI = 0.61–0.85; P < 0.0001; HR = 0.83; 95% CI = 0.75–0.92; P = 0.0002); however, no differences were observed in terms of OS and DFS between HER2-low and HER2-zero BC in the HR-negative group. In the HR-positive group, HER2-low status had no significant impact on OS, while significantly associated with increased DFS (HR = 0.85; 95% CI = 0.76–0.96; P = 0.007). Conclusion: These results suggest that although HER2-low BC has a poor response to NACT, it is correlated with favorable OS and DFS after NACT in the overall cohort as well as longer DFS in the HR-positive group. [ABSTRACT FROM AUTHOR]

Objectives Micro RNAs (mi RNAs) contribute to control of cell cycle progression and are frequently deregulated in cancer. The focus of this study was to determine effects of miR-142-3p on the cell cycle progression and cancer cell proliferation. Materials and methods RT- qPCR was performed to determine expression of miR-142-3p in a range of cancer cell lines and in clinical cancer specimens. To further understand its role, we restored its expression in cancer cell lines by transfection with miR-142-3p mimics or inhibitors. Effects of miR-142-3p on cell cycle progression and cell proliferation were also determined. Results miR-142-3p was down-regulated in both cancer cell lines and cancer specimens. Its overexpression suppressed proliferation, whereas its depletion promoted it. In addition, miR-142-3p lead to cell cycle arrest in G2/M. Moreover, CDC25C was identified as being a target of miR-142-3p, ectopic expression of which reversed suppression of cell proliferation. Conclusions Our observations suggest that miR-142-3p functioned as a tumor suppressor by targeting CDC25C. [ABSTRACT FROM AUTHOR]

Purpose: The aquaporin (AQP) family consists of a number of small integral membrane proteins that transport water and glycerol. AQPs are critical for trans-epithelial fluid transport. Recent reports demonstrated that AQPs, particularly AQP1 and AQP5, are expressed in high grade tumor cells of a variety of tissue origins, and that AQPs are involved in cell migration and metastasis. Based on this background, we examined whether AQP3, another important member of the AQP family, could facilitate cell migration in human breast cancers. Methods: Potential role of AQP3 was examined using two representative breast cancer cell lines (MDA-MB-231 and Bcap-37). Briefly, AQP3 expression was inhibited with a lentivirus construct that stably expressed shRNA against the AQP3 mRNA. AQP3 expression inhibition was verified with Western blot. Cell migration was examined using a wound scratch assay in the presence of fibroblast growth factor-2 (FGF-2). In additional experiments, AQP3 was inhibited by CuSO4. Fibroblast growth factor receptor (FGFR) kinase inhibitor PD173074, PI3K inhibitor LY294002, and MEK1/2 inhibitor PD98059 were used to dissect the molecular mechanism of FGF-2 induced AQP3 expression. Results: FGF-2 treatment increased AQP3 expression and induced cell migration in a dose dependent manner. Silencing AQP3 expression by a lentiviral shRNA inhibited FGF-2 induced cell migration. CuSO4, a water transport inhibitor selective for AQP3, also suppressed FGF-2-induced cell migration. The FGFR kinase inhibitor PD173074, significantly inhibited FGF-2-induced AQP3 expression and cell migration. The PI3K inhibitor LY294002 and MEK1/2 inhibitor PD98059 inhibited, but not fully blocked, FGF-2-induced AQP3 expression and cell migration. Conclusions: AQP3 is required for FGF-2-induced cell migration in cultured human breast cancer cells. Our findings also suggest the importance of FGFR-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression. In summary, our findings suggest a novel function of AQP3 in cell migration and metastasis of breast cancers. [ABSTRACT FROM AUTHOR]

miRNAs, a major class of small noncoding RNAs approximately 18–25 nucleotides in length, function by repressing the expression of target genes through binding to complementary sequences in the 3′-UTRs of target genes. Emerging evidence has highlighted their important roles in numerous diseases, including human cancers. Recently, miR-190 has been shown to be dysregulated in various types of human cancers that participates in cancer-related biological processes, including proliferation, apoptosis, metastasis, drug resistance, by regulating associated target genes, and to predict cancer diagnosis and prognosis. In this review, we summarized the roles of miR-190-5p in human diseases, especially in human cancers. Then we classified its target genes in tumorigenesis and progression, which might provide evidence for cancer diagnosis and prognosis, promising tools for cancer treatment, or leads for further investigation. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy with dual-targeted therapy is the standard treatment for human epidermal growth factor 2 (HER2)-positive breast cancer. Although the dual-targeted therapy has significantly improved the pathological complete response (pCR) rate, further investigation is needed to identify biomarkers that predict the response to neoadjuvant therapy. Methods: This retrospective study analyzed 353 patients with HER2-positive breast invasive ductal carcinoma. The correlation between clinicopathological factors and pCR rate was evaluated. A nomogram was constructed based on the results of the multivariate logistic regression analysis to predict the probability of pCR. Results: The breast pCR (b-pCR) rate was 56.1% (198/353) and the total pCR (t-pCR) rate was 52.7% (186/353). Multivariate analysis identified ER status, PR status, HER2 status, Ki-67 index, and neoadjuvant chemotherapy regimens as independent indicators for both b-pCR and t-pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.73 (95% CI: 0.68–0.78). According to the nomogram, the t- pCR rate was highest in the ER-PR- HER2-positive patients (131/208) and lowest in the ER + PR + HER2-positive patients (19/73). The subgroup analyses showed that there was no significant difference in pCR rate among the neoadjuvant chemotherapy regimens in ER positive, PR positive, HER2 IHC 2 + , Ki67 index < 30% population. However, for ER-PR-HER2-positive patients, the neoadjuvant chemotherapy regimen has a great influence on the pCR rates. Conclusions: Patients with ER-negative, PR-negative, HER2 3 + and high KI-67 index were more likely to achieve pCR. THP may be used as an alternative to AC-THP or TCbHP in selected HER2-positive patients. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain. Methods: We identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP. Results: PAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3'UTR region, respectively. Conclusion: In summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: Surgical meshes are often used in retro-pectoral implant-based breast reconstruction (IBBR) to improve lower pole expansion. However, using of surgical meshes is associated with increased complications and costs. To solve this problem, we have adopted a modified fascia-based IBBR technique using fasciae of pectoral major, serratus anterior, and external oblique muscles to form a sling covering the lower pole of prosthesis since 2014. Methods: Data of 788 retro-pectoral IBBR cases, including 250 fascia-based IBBR cases (fascial group) and 538 traditional IBBR cases (control group), treated between 2014 and 2019 were retrospectively analyzed. The surgical outcomes of the fascial and control group were compared. The primary endpoint was the rate of post-operative complications requiring interventions. The secondary endpoint was the rate of explantation. The exploratory endpoint was the time from surgery to complication and explantation. Results: The fascial group had significantly lower rates of developing major post-operative complications (1.2 vs. 6.1%, p = 0.002) and losing prostheses (1.2 vs. 4.3%, p = 0.025), as compared with the control group. The median time from surgery to complication and explantation were 61 (range, 35–115) days and 92 (range, 77–134) days for the fascial group and 35 (range, 6–239) days and 63 (range, 23–483) days for the control group, respectively. Conclusion: Fascia-based IBBR technique had low rates of major post-operative complications and explantation. Fascia-based IBBR technique could be considered as an alternative reconstruction method in properly selected patients. [ABSTRACT FROM AUTHOR]

Tamoxifen is commonly used for the treatment of patients with estrogen receptor‐positive (ER+) breast cancer, but the acquired resistance to tamoxifen presents a critical challenge of breast cancer therapeutics. Recently, long noncoding RNA MIR497HG and its embedded miR‐497 and miR‐195 are proved to play significant roles in many types of human cancers, but their roles in tamoxifen‐resistant breast cancer remain unknown. The results indicate that MIR497HG deficiency induces breast cancer progression and tamoxifen resistance by inducing downregulation of miR‐497/195. miR‐497/195 coordinately represses five positive PI3K‐AKT regulators (MAP2K1, AKT3, BCL2, RAF1, and CCND1), resulting in inhibition of PI3K‐AKT signaling, and PI3K‐AKT inhibition in tamoxifen‐resistant cells restored tamoxifen responsiveness. Furthermore, ER α binds the MIR497HG promoter to activate its transcription in an estrogen‐dependent manner. ZEB1 interacts with HDAC1/2 and DNMT3B at the MIR497HG promoter, resulting in promoter hypermethylation and histone deacetylation. The findings reveal that ZEB1‐induced MIR497HG depletion contributes to breast cancer progression and tamoxifen resistance through PI3K‐AKT signaling. MIR497HG can be used as a biomarker for predicting tamoxifen sensitivity in patients with ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) remains the leading cause of cancer‐related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. Methods: In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2‐negative breast invasive ductal carcinoma. According to the expression level of PR and Ki‐67 index, the Luminal B (HER2‐negative) BCs were divided into three groups: ER+PR−Ki67low (ER‐positive, PR‐negative, and Ki‐67 index <20%), ER+PR+Ki67high (ER‐positive, PR‐positive, and Ki‐67 index ≥20%), and ER+PR−Ki67high (ER‐positive, PR‐negative, and Ki‐67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log‐rank χ2 value. Results: The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease‐free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR−Ki67high subgroup have the worst survival outcome in Luminal B (HER2‐negative) subtype, similar to Triple‐negative patients. Besides, the ER+PR+Ki67high has worse 5‐year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR–Ki67high subtype were more likely to have high RI for distance recurrence (RI‐DR) and local recurrence (RI‐LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2‐negative) BC patients, which may help in clinical decision‐making for individual treatment. [ABSTRACT FROM AUTHOR]

Background. Thyroid cancer (TC) tends to be a common malignancy worldwide and results in various outcomes due to its different subtypes. The tumor microenvironment (TME) was demonstrated to play crucial roles in various malignancies, including thyroid cancer. This study combined the ESTIMATE and CIBERSORT algorithms, identified four TME-related genes, and evaluated their correlation with clinical characteristics. These findings revealed the malignant performance of TME in TC, and the TME-related DEGs might serve as prognostic biomarkers, which can be utilized for the prediction of immunotherapy effects in patients with TC. Methods. The clinical and gene expression profiles of TC patients were collected from the TCGA dataset. The ESTIMATE algorithm was utilized to estimate stromal and immune scores and predict the level of stromal and immune cell infiltration. The differential expressed genes related to TME were filtered by the "limma" package in R, and the PPI network was constructed by a string website. KEGG pathway and GO analyses were performed to investigate the biological progression and molecular functions of TME-related DEGs. Then, univariate Cox regression analysis was employed to screen four genes correlated with clinical characteristics. GSEA was conducted to assess their roles in the TME of TC. To further investigate the association between TME-related genes and tumor-infiltrating immune cells (TIICs), the CIBERSORT algorithm was performed. Finally, the malignancy behaviors of the two genes were verified by RT-qPCR, IHC, MTT, colony formation, and transwell assays. Results. Four TME-related DEGs, LRRN4CL, HS3ST3A1, PCOLCE2, and CAPN8, were identified and were significantly predictive of poor overall survival. KEGG and GO pathway analysis established that the TME-related DEGs were involved in immune responses and pathways in cancer. Furthermore, the malignancy behaviors of HS3ST3A1 and CAPN8 were verified by cellular functional experiments. These results revealed that the TME-related genes HS3ST3A1 and CAPN8 were able to serve as predictors of prognosis in patients with TC. Conclusion. HS3ST3A1 and CAPN8 may serve as valuable prognostic biomarkers and TME indicators, which can be utilized for the prediction of immunotherapy effects and provide novel treatment strategies for patients with TC. [ABSTRACT FROM AUTHOR]

Background: Breast cancer remains the most common malignancy in females around the world. Recently, a growing number of studies have focused on gene dysregulation. In our previous study, Krüppel‐like factors (KLFs) were found to play essential roles in breast cancer development, among which KLF2 could function as a tumor suppressor. Nevertheless, the underlying molecular mechanism remains unclear. Methods: miR‐92a‐3p was identified as the upstream regulator of KLF2 by starBase v.3.0. The regulation of KLF2 by miR‐92a‐3p was verified by a series of in vitro and in vivo assays. Further exploration revealed that Baculoviral IAP Repeat Containing 5 (BIRC5) was the target of KLF2. ChIP assay, dual‐luciferase reporter analysis, quantitative real‐time PCR, and western blot were performed for verification. Results: miR‐92a‐3p functioned as a tumor promoter by inhibiting KLF2 by binding to its 3'‐untranslated region (3'‐UTR). In addition, KLF2 could transcriptionally suppress the expression of BIRC5. Conclusion: Collectively, our results uncovered the miR‐92a‐3p/KLF2/BIRC5 axis in breast cancer and provided a potential mechanism for breast cancer development, which may serve as promising strategies for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms. Methods: CCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects. Results: We noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384–ZEB1 in breast cancer metastasis. Conclusions: The findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population.Methods: Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer.Results: Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+  = 1.47, 95% CI: 1.19, 1.80; ORPR+  = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21).Conclusions: Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy is a practical locoregional treatment approach for women with breast cancer who show ipsilateral supraclavicular lymph node metastasis (ISLNM) on diagnosis. However, there is controversy around the role of supraclavicular lymph node dissection. Therefore, we aimed to study the significance of supraclavicular surgery based on radiotherapy.Patients and Methods: We retrospectively reviewed the data of 142 patients with breast cancer who presented with isolated ISLNM and received radiotherapy between the years 2000 and 2016. We also defined the effect of surgery on locoregional treatment of these patients by analyzing the prognostic factors for recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS).Results: We observed that, of the 142 patients, 104 who received radiotherapy underwent supraclavicular lymph node dissection. Also, among the study group, the progesterone receptor (PR) status (P = 0.044) and the number of axillary lymph nodes (ALNs) involved (P = 0.002) were significant independent predictors of RFS. Also, tumor size (P = 0.007), PR (P < 0.001), and number of ALNs (P < 0.001) were independent predictors of DMFS and were statistically significant. Also, PR was an independent prognostic factor of OS (P = 0.033), whereas the supraclavicular surgery was not an independent prognostic factor for RFS, DMFS, and OS. Furthermore, our study focused on 92 patients with negative estrogen receptors (ERs). The result showed that supraclavicular surgery was statistically significant for RFS (P = 0.023); no significant differences in DMFS and OS were found between patients who received supraclavicular surgery and those who did not.Conclusion: Radiotherapy may be the primary locoregional treatment approach for patients with breast cancer who present with newly diagnosed ISLNM. Additionally, supraclavicular surgery may be more appropriate for patients with negative ER who received radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Krüppel‐like factors (KLFs) are zinc finger proteins which participate in transcriptional gene regulation. Although increasing evidence indicate that KLFs are involved in carcinogenesis and progression, its clinical significance and biological function in breast cancer are still limited. Methods: We investigated all the expression of KLFs (KLF1-18) at transcriptional levels by using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). The mRNA and protein expression levels of KLFs were also determined by using RT-qPCR and immunohistochemistry, respectively. CBioPortal, GeneMANIA and STRING were used to comprehensive analysis of the molecular characteristics of KLFs. The clinical value of prognostic prediction based on the expression of KLFs was determined by using the KM plotter. The relevant molecular pathways of KLFs were further analyzed by using Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Finally, we investigated the effect of KLF2 and KLF15 on biological behavior of breast cancer cells in vitro. Results: The expression of KLF2/4/6/8/9/11/15 was significantly down-regulated in breast cancer. The patients with high KLF2, KLF4 or KLF15 expression had a better outcome, while patients with high KLF8 or KLF11 had a poor prognosis. Furthermore, our results showed that KLF2 or KLF15 can be used as a prognostic factor independent on the other KLFs in patients with breast cancer. Overexpression of KLF2 or KLF15 inhibited cell proliferation and migration, and blocked cell cycle at G0/G1 phase, resulting in cell apoptosis. Conclusions: KLF2 and KLF15 function as tumor suppressors in breast cancer and are potential biomarkers for prognostic prediction in patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: N6-Methyladenosine (m6A) is the most common RNA modification and regulates RNA splicing, translation, translocation, and stability. Aberrant expression of m6A has been reported in various types of human cancers. m6A RNA modification is dynamically and reversibly mediated by different regulators, including methyltransferase, demethylases, and m6A binding proteins. However, the role of m6A RNA methylation regulators in thyroid cancer remains unknown. The aim of this study is to investigate the effect of the 13 main m6A RNA modification regulators in thyroid carcinoma. Methods: We obtained clinical data and RNA sequencing data of 13 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) THCA database. We performed consensus clustering to identify the clinical relevance of m6A RNA methylation regulators in thyroid carcinoma. Then we used LASSO Cox regression analysis to generate a prognostic signature based on m6A RNA modification regulator expression. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Gene Set Enrichment Analyses were performed to explore differential cellular processes and signaling pathways between the two groups based on risk signature. Results: We found that most of the m6A RNA modification regulators are down-regulated in 450 patients with thyroid carcinoma. We derived a three m6A RNA modification regulator genes-based risk signature (FTO, RBM15 and KIAA1429), that is an independent prognostic biomarker in patients with thyroid carcinoma. Moreover, we found that this risk signature could better predict outcome in male than female. Functional research in vitro demonstrated that the m6A RNA methylation regulators involved in the model acted significant role in the proliferation and migration of thyroid cancer cells. Conclusions: Our study revealed the influence of m6A RNA methylation regulators on thyroid carcinoma through biological experiments and three-gene prognostic model. [ABSTRACT FROM AUTHOR]

Background: X‐ray repair cross‐complementary 5 (XRCC5) and 6 (XRCC6) are critical for DNA repair. Few studies have assessed their association with breast cancer risk, and related gene‐environment interactions remain poorly understood. This study aimed to determine the influence of XRCC5/6 polymorphisms on breast cancer risk, and their interactions with cigarette smoking, alcohol consumption, and sleep satisfaction. Methods: The study included 1039 patients with breast cancer and 1040 controls. Four single‐nucleotide polymorphisms of XRCC5 and two of XRCC6 were genotyped. Information about smoking, alcohol consumption, and sleep satisfaction was collected through questionnaires. Odds ratios (OR) and related 95% confidence intervals (95% CI) were assessed using unconditional logistic regression models. Gene‐environment interactions were analyzed using logistic regression with multiplicative interaction models. Results: XRCC5 rs16855458 was associated with increased breast cancer risk in the co‐dominant (ptrend = 0.003) and dominant (CA + AA vs. CC, OR = 1.29, 95% CI = 1.07–1.56, p = 0.008) genetic models after Bonferroni correction. The CG + GG genotype of XRCC6 rs2267437 was associated with an increased risk of estrogen receptor‐negative/progesterone receptor‐negative (ER−/PR−) breast cancer (CG + GG vs. CC: OR = 1.54, 95% CI = 1.12–2.13, p = 0.008) after Bonferroni correction. Moreover, an antagonistic interaction between XRCC5 rs16855458 and alcohol consumption (pinteraction = 0.017), and a synergistic interaction between XRCC6 rs2267437 and sleep satisfaction were associated with breast cancer risk (pinteraction = 0.0497). However, these interactions became insignificant after Bonferroni correction. Conclusion: XRCC5 rs16855458 was associated with breast cancer risk, and XRCC6 rs2267437 was associated with the risk of ER−/PR− breast cancer. Breast cancer risk associated with XRCC5 and XRCC6 polymorphisms might vary according to alcohol consumption and sleep satisfaction, respectively, and merit further investigation. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide. Chemoresistance remains to be a considerable obstacle in breast cancer therapy and it is often involves dysregulation of a variety of microRNAs (miRNAs). miR-485-5p functions as a tumor suppressor in several types of human cancers. However, its role in breast cancer chemosensitivity have not been determined. In the present study, we demonstrated that overexpression of miR-485-5p suppresses breast cancer progression and enhances chemosensitivity both in vitro and in vivo . Further study demonstrated that miR-485-5p directly targeted the 3′-untranslated region of survivin and overexpression of survivin overcomes the miR-485-5p induced effects on breast cancer. In conclusion, our study identified that miR-485-5p suppresses cancer progression and enhances the chemosensitivity by targeting survivin. Targeting survivin by miR-485-5p may provide a potential approach to reverse chemosensitivity in breast cancer cells. [ABSTRACT FROM AUTHOR]

The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer (P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk (P=0.020, 0.014, 0.035) in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk (P=0.034, 0.0116). This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed. [ABSTRACT FROM AUTHOR]

Highlights: [•] PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. [•] PCDH7 is up-regulation in bone metastatic breast cancer tissues. [•] Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. [•] PCDH7 induces breast cancer bone metastasis in vivo. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of Akt/ARK5 pathways on the metastatic potential of human breast cancer cells. Materials and methods: The human ARK5 gene was transfected into MDA-MB-231 cells. Effects of ARK5 on MDA-MB-231 cells were investigated in vitro. The tumorigenicity and spontaneously metastatic capability regulated by ARK5 were determined using an orthotopic xenograft tumor model. Results: ARK5 enhanced the invasive and metastatic potential of MDA-MB-231 cells under regulation by Akt. The enhancement was associated with increasing MMP-2, MMP-9, and MT1-MMP expression. The results were further demonstrated by RNA interference experiment. In an in vivo study, we also demonstrated that ARK5-transfected breast cancer cells grew faster and had more pulmonary metastases than its parental counterparts. Conclusion: ARK5 led to a more invasive phenotype and metastatic potential in human breast cancer dependent on Akt. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-β (TGF-β) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. Methods: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. Results: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-β-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. Conclusions: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-β network in breast cancer progression. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. Therapies targeting ERα have been successfully used in patients with ERα+ breast cancer. However, intrinsic or acquired resistance to anti-estrogen therapy presents a major challenge. The Wnt/β-catenin signaling pathway regulates various processes that are important for cancer progression, and emerging evidences have shown a close interaction between Wnt/β-catenin and ERα signaling. miR-190 is also involved in ER signaling and our previous study indicated that miR-190 suppresses breast cancer metastasis. Methods: The effect of miR-190 on breast cancer anti-estrogen sensitivity was investigated both in vitro and in vivo. The protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of the zinc-finger E-box binding homeobox 1/ ERα-miR-190-SRY-related high mobility group box 9 (ZEB1/ERα-miR-190-SOX9) axis. Results: miR-190 increased the anti-estrogen sensitivity of breast cancer cells both in vitro and in vivo. miR-190 inhibited Wnt/β-catenin signaling by targeting SOX9, and its expression inversely correlated with that of SOX9 in breast cancer samples. Furthermore, ERα and ZEB1 competitively regulated miR-190 expression. Conclusions: Our data uncover the ZEB1/ERα-miR-190-SOX9 axis and suggest a mechanism by which the Wnt/β-catenin signaling pathway is involved in breast cancer anti-estrogen therapy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer among women worldwide and metastasis is the leading cause of death among patients with breast cancer. The transforming growth factor-β (TGF-β) pathway plays critical roles during breast cancer epithelial–mesenchymal transition (EMT) and metastasis. SMAD2, a positive regulator of TGF-β signaling, promotes breast cancer metastasis through induction of EMT. Methods: The expression of miR-190 and SMAD2 in breast cancer tissues, adjacent normal breast tissues and cell lines were determined by RT-qPCR. The protein expression levels and localization were analyzed by western blotting and immunofluorescence. ChIP and dual-luciferase report assays were used to validate the regulation of ZEB1-miR-190-SMAD2 axis. The effect of miR-190 on breast cancer progression was investigated both in vitro and in vivo. Results: miR-190 down-regulation is required for TGF-β-induced EMT. miR-190 suppresses breast cancer metastasis both in vitro and in vivo by targeting SMAD2. miR-190 expression is down-regulated and inversely correlates with SMAD2 in breast cancer samples, and its expression level was associated with outcome in patients with breast cancer. Furthermore, miR-190 is transcriptionally regulated by ZEB1. Conclusions: Our data uncover the ZEB1-miR-190-SMAD2 axis and provide a mechanism to explain the TGF-β network in breast cancer metastasis. [ABSTRACT FROM AUTHOR]

The glutathione-S-transferase (GST) family contributes to the inactivation of various toxic compounds formed as secondary metabolites during oxidative stress. GSTP1 accounts for the majority of the GST family enzymatic activity, and the activity of GSTP1 enzyme can be altered by the presence of the Ile105Val polymorphism. In this study, we examined the polymorphic frequency of GSTP1 Ile105Val genotype in 920 breast cancer patients and 783 healthy controls in women of North China. Results showed that GSTP1 105Val allele (Ile/Val and Val/Val) was associated with a higher breast cancer risk (OR = 1.38, 95% CI: 1.14–1.69; P = 0.001) and more aggressive tumors with histological grade III (OR = 1.15, 95% CI: 1.05–1.26; P = 0.001), lymph node metastases (OR = 2.35, 95% CI: 1.72–3.21; P < 0.001), as well as ER negative (OR = 1.77, 95% CI: 1.31–2.39; P < 0.001) than those carrying the Ile/Ile allele. However, the patients with the GSTP1 105Val genotype had a better disease free survival after cyclophosphamide (CTX)-based chemotherapy than those with Ile/Ile (HR = 0.77, 95% CI: 0.45–0.91; P < 0.001). Furthermore, in vitro cellular experiments demonstrated that breast cancer cells with the GSTP1 105Val allele were significantly more sensitive to CTX-induced proliferation inhibition. Thus, we conclude that the GSTP1 105Val allele increases breast cancer risk and aggressiveness and enhance response to CTX-based chemotherapy in women of North China. Detection of the GSTP1 Ile105Val genotype may help screen for high-risk populations and direct individualized therapy. [ABSTRACT FROM AUTHOR]