Poor Prognosis In Breast Cancer Research Articles

Tumor-Associated Macrophages as Multifaceted Regulators of Breast Tumor Growth.

Breast cancer is the most commonly occurring cancer in women of Western countries and is the leading cause of cancer-related mortality. The breast tumor microenvironment contains immune cells, fibroblasts, adipocytes, mesenchymal stem cells, and extracellular matrix. Among these cells, macrophages or tumor-associated macrophages (TAMs) are the major components of the breast cancer microenvironment. TAMs facilitate metastasis of the breast tumor and are responsible for poor clinical outcomes. High TAM density was also found liable for the poor prognosis of breast cancer. These observations make altering TAM function a potential therapeutic target to treat breast cancer. The present review summarizes the origin of TAMs, mechanisms of macrophage recruitment and polarization in the tumor, and the contributions of TAMs in tumor progression. We have also discussed our current knowledge about TAM-targeted therapies and the roles of miRNAs and exosomes in re-educating TAM function.

Maximum slope using ultrafast breast DCE-MRI at 1.5 Tesla: a potential tool for predicting breast lesion aggressiveness.

We evaluated the relationship between the maximum slope (MS) based on ultrafast breast DCE-MRI sequences, and the clinical parameters and routine prognostic factors of breast cancer. 210 lesions were retrospectively evaluated: 150 malignant (30 each of luminal A invasive carcinoma, luminal B invasive carcinoma, HER2 overexpression (HER2), triple negative (TN), invasive lobular carcinoma (ILC)), and 60 benign. For each lesion, the MS was obtained with an ultrafast sequence and semi-quantitative curves were classified into three types with a conventional DCE sequence. The correlation between MS and age, body mass index (BMI), menopause, and routine prognostic factors were analyzed. A MS cut-off at 6.5%/s could discriminate benign from malignant lesions, with sensitivity and specificity of 84% and 90%, respectively, whereas analysis of semi-quantitative curves showed sensitivity and specificity of 89.3% and 55%, respectively. In multivariate analysis, MS values decreased with BMI increasing (p = 0.035), postmenopausal status (p < 0.001), and positive ER status (p < 0.001) and increased with tumor size (p < 0.001). The MS was significantly lower for the pooled luminal A + ILC group than for the pooled luminal B + HER2 + TN group featuring tumors with poorer prognoses (p < 0.001). With a threshold of 11%/s, the sensitivity and specificity to identify invasive carcinoma subtypes with poorer prognoses were 71% and 68%, respectively. The MS allows better tumor characterization and identifies factors of poor prognosis for breast cancer. • Maximum slope calculated from ultrafast breast DCE-MRI differentiates benign from malignant breast lesions better than semi-quantitative curves of conventional DCE-MRI. • Maximum slope calculated from ultrafast breast DCE-MRI identifies breast cancers with poor prognoses. • In the case of multiple lesions, the most aggressive may be identified and targeted by measuring the maximum slope.

LRRC3B Polymorphisms Contributed to Breast Cancer Susceptibility in Chinese Han Population.

Purpose LRRC3B gene, as a tumor suppressor gene was involved in the development and progress of breast cancer (BC). However, the effect of LRRC3B polymorphisms on BC has rarely been reported. In the study, we aimed to evaluate the relation between LRRC3B variants and BC risk.MethodsAmong 563 BC patients and 552 healthy controls, ten single-nucleotide polymorphisms (SNPs) in LRRC3B were genotyped by Agena MassARRAY. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using logistic regression model.ResultsOur study demonstrated that rs1907168 polymorphism (heterozygous: OR = 0.71, p = 0.017) was related to the reduced risk of BC in the overall. In stratified analyses by age, rs1907168 was associated with the decreased (heterozygous: OR = 0.53, p = 0.002) while rs78205284 (homozygote: OR = 2.83, p = 0.034) increased BC susceptibility among the population at age ≤51 years. Rs6551122 (recessive: OR = 0.51, p = 0.028) and rs12635768 (homozygote, OR = 0.36, p = 0.023) polymorphisms were related to the smaller BC tumor size (<2 cm). In addition, rs112276562 (heterozygote OR = 0.56, p = 0.002), rs6551122 (heterozygote OR = 0.63, p = 0.016), and rs73150416 (heterozygote OR = 0.57, p = 0.005) variants contributed to the lower incidence of PR-positive BC. Moreover, rs6788033 was associated with a lower expression level of Ki-67 (log-additive: OR = 0.68, p = 0.024). Furthermore, we found an association of ‘GATT’ haplotype with an increased risk for BC. In addition, LRRC3B gene was down-regulated in BC tumor and had a poor prognosis in BC in in silico analysis.ConclusionOur study firstly found LRRC3B SNPs contributed to the risk of BC, suggesting LRRC3B variants might help to predict BC progression.

Diabetes Risk Reduction Diet and Survival after Breast Cancer Diagnosis.

Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer-specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65-0.97; P trend = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58-0.76; P trend < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer-specific mortality (HR = 0.77; 95% CI = 0.62-0.95) and overall mortality (HR = 0.85; 95% CI = 0.74-0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors. SIGNIFICANCE: This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.

PFKFB4 Overexpression Facilitates Proliferation by Promoting the G1/S Transition and Is Associated with a Poor Prognosis in Triple-Negative Breast Cancer.

Background 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. Methods First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. Results We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. Conclusions These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.

Overexpression of SOX2 is associated with poor prognosis in human breast cancer

SOX2 is a transcription factor that activates or suppresses genes involved in cellular differentiation, proliferation, and apoptosis. The deregulation of gene expression programs can lead to cancer initiation, promotion, and progression. The present study investigated SOX2 immunolocalization and expression in Invasive Ductal Carcinoma (IDC), and its correlation with clinical-pathological characteristics of the tumor. Immunohistochemical expression of SOX2 was evaluated in 19 cases of IDC and correlated with clinical-pathological tumor features. To investigate the correlation of SOX2 expression in IDC with other characteristics of human breast cancer, the same samples were also stained with immunohistochemical prognostic panels (estrogen and progesterone receptors, and HER-2). SOX2 overexpression was observed in 44% of the cases. Higher SOX2 expression was correlated with the worst lymph node status (p&lt;0.001) and with positive HER-2 immunostaining (p&lt;0,001). The present study demonstrated the association of SOX2 and tumors with worse TNM staging, as well as its overexpression in positive HER-2 tumors. In conclusion, SOX2 was identified as a potential biomarker for poor prognosis of human breast cancer. Further studies with higher patient numbers are necessary to investigate and help clarify the mechanisms underlying this association. Keywords: SOX2; HER-2; Breast cancer; IHC; Invasive ductal carcinoma; Prognosis.

Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

BackgroundPreviously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients.MethodsIn total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was also examined.ResultsThe relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells.ConclusionsIn ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

Study of Gene Expression of Programmed Cell Death Ligand 1 (PD-L1) in Breast Cancer Patients

Introduction: Breast cancer is the most frequently occurring cancer among females and the second most common cancer overall. Programmed Cell Death Ligand 1 (PD-L1) plays an important role in blocking ‘cancer-immunity cycle’ and is considered as a major inhibitory pathway. The aim of the present study was to clarify the alterations of expression of PD-L1 in peripheral blood mononuclear cytes (PBMCs) of female breast cancer patients and analyze its association with clinico-pathological criteria as well as therapeutic response. Materials and Methods: The study was conducted on 45 female breast cancer patients and 45 female controls. Blood samples were collected followed by PBMCs isolation, total RNA extraction, reverse transcription and finally, quantitative polymerase chain reaction (qPCR) using SYBR Green DNA binding dye. Expression levels of PD-L1 were calculated and then compared with clinicopathological parameters of the patients in addition to initial therapeutic response. Results: A significant difference was detected for PD-L1 expression levels in breast cancer patients compared to controls. A significant association with age, metastatic breast cancer, estrogen receptor (ER) negative status as well as high concentrations of cancer antigen 15-3 (CA15-3) was detected. On the other hand, no significant association was recognized with tumor size, lymph nodal status, histopathological type, grade, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER-2) status, triple negative, among de novo and recurrent metastatic patients and for the number of metastatic sites as well as the therapeutic response. Conclusions: This study paves the way of the use of PD-L1 as a noninvasive prognostic and diagnostic biomarker for poor prognosis of breast cancer.

Cleavage of Syndecan-1 Promotes the Proliferation of the Basal-Like Breast Cancer Cell Line BT-549 Via Akt SUMOylation.

Basal-like breast cancer is characterized by an aggressive clinical outcome and presence of metastasis, for which effective therapies are unavailable. We have previously shown that chondroitin 4-O-sulfotransferase-1 (C4ST-1) controls the invasive properties of the basal-like breast cancer cell line BT-549 by inducing matrix metalloproteinase (MMP) expression through the N-cadherin/β-catenin pathway. Here we report that C4ST-1 controls the proliferation of BT-549 cells via the MMP-dependent cleavage of syndecan-1. Syndecan-1 is a membrane-bound proteoglycan associated with an aggressive phenotype and poor prognosis in breast cancer. In addition, the cleavage of syndecan-1 at a specific juxtamembrane cleavage site is implicated in the pathophysiological response in breast cancer. Knockout of C4ST-1 remarkably suppressed both the cleavage of syndecan-1 and proliferation of BT-549 cells. Kinases (AKT1, ERK1/2, PI3K, and STAT3) comprising cancer proliferative pathways are phosphorylated in C4ST-1 knockout cells at a level similar to that in parental BT-549 cells, whereas levels of phosphorylated S6 kinase and SUMOylated AKT (hyperactivated AKT observed in breast cancer) decreased in C4ST-1 knockout cells. An MMP inhibitor, GM6001, suppressed the small ubiquitin-like modifier (SUMO) modification of AKT, suggesting that cleavage of syndecan-1 by MMPs is involved in the SUMO modification of AKT. Forced expression of the cytoplasmic domain of syndecan-1, which is generated by MMP-dependent cleavage, increased the SUMO modification of AKT and global protein SUMOylation. Furthermore, syndecan-1 C-terminal domain-expressing BT-549 cells were more proliferative and sensitive to a potent SUMOylation inhibitor, tannic acid, compared with BT-549 cells transfected with an empty expression vector. These findings assign new functions to the C-terminal fragment of syndecan-1 generated by MMP-dependent proteolysis, thereby broadening our understanding of their physiological importance and implying that the therapeutic inhibition of syndecan-1 cleavage could affect the progression of basal-like breast cancer.

DCTPP1, an Oncogene Regulated by miR-378a-3p, Promotes Proliferation of Breast Cancer via DNA Repair Signaling Pathway.

Breast cancer (BRCA) is one of the most deadly cancers worldwide, with poor survival rates that could be due to its high proliferation. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is implicated in numerous diseases, including cancers. However, its role in BRCA is unclear. In this study, we used bioinformatic analyses of the ONCOMINE, UALCAN, and GEPIA databases to determine the expression pattern of DCTPP1 in BRCA. We found that elevated DCTPP1 levels correlate with poor BRCA prognosis. DCTPP1 silencing inhibited BRCA cell proliferation and induced apoptosis in vitro, as well as in vivo. Our data show that this tumorigenic effect depends on DNA repair signaling. Moreover, we found that DCTPP1 is directly modulated by miR-378a-3p, whose downregulation is linked to BRCA progression. Our results showed down-regulation of miR-378a-3p in BRCA. Upregulation of miR-378a-3p, on the other hand, can inhibit BRCA cell growth and proliferation. This study shows that reduced miR-378a-3p level enhances DCTPP1 expression in BRCA, which promotes proliferation by activating DNA repair signaling in BRCA.

Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late-stage breast cancer.

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III–IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08–5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.

Investigating survivin as a novel target in black women with breast cancer.

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p &lt; 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]

Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.

e12586 Background: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early-stage breast cancer in China. Methods: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman’s correlation analysis, while the impact of TOP2A expression on disease free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. Results: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low-expression. TOP2A over-expression was in positive associations with a higher ki67 index (r = 0.83, P &lt; 0.001), HER2 positive (r = 0.24, P &lt; 0.001), a larger tumor size (r = 0.15, P &lt; 0.001), and a higher histologic grade (r = 0.59, P &lt; 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression in early breast cancer (r = -0.40, P &lt; 0.001). TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P &lt; 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 1.71; 95% confidence interval [95%CI]: 1.13-2.59, P = 0.02) and OS (HR = 3.53; 95%CI: 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. Conclusions: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, ki67 index, tumor size, histologic grade, and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.

SCUBE3 serves as an independent poor prognostic factor in breast cancer

BackgroundAccumulating evidences indicate that the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) plays a key role in the development and progression of many human cancers. However, the underlying mechanism and prognosis value of SCUBE3 in breast cancer are still unclear.MethodsThe clinical data of 137 patients with breast cancer who underwent surgical resection in Taizhou Hospital of Zhejiang Province were retrospectively analyzed. We first conducted a comprehensive study on the expression pattern of SCUBE3 using the Tumor Immune Estimation Resource (TIMER) and UALCAN databases. In addition, the expression of SCUBE3 in breast tumor tissues was confirmed by immunohistochemistry. The protein–protein interaction analysis and functional enrichment analysis of SCUBE3 were analyzed using the STRING and Enrichr databases. Moreover, tissue microarray (TMA) was used to analyze the relationship between SCUBE3 expression levels and clinical-pathological parameters, such as histological type, grade, the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). We further supplemented and identified the above results using the UALCAN and bc-GenExMiner v4.4 databases from TCGA data. The correlation between the expression of SCUBE3 and survival was calculated by multivariate Cox regression analysis to investigate whether SCUBE3 expression may be an independent prognostic factor of breast cancer.ResultsWe found that the expression level of SCUBE3 was significantly upregulated in breast cancer tissue compared with adjacent normal tissues. The results showed that the distribution of breast cancer patients in the high expression group and the low expression group was significantly different in ER, PR, HER2, E-cadherin, and survival state (p < 0.05), but there was no significant difference in histologic grade, histologic type, tumor size, lymph node metastasis, TMN stage, subtypes, or recurrence (p > 0.05). In addition, the high expression of SCUBE3 was associated with relatively poor prognosis of ER- (p = 0.012), PR- (p = 0.029), HER2 + (p = 0.007). The multivariate Cox regression analysis showed that the hazard ratio (HR) was 2.80 (95% CI 1.20–6.51, p = 0.0168) in individuals with high SCUBE3 expression, and HR was increased by 1.86 (95% CI 1.06–3.25, p = 0.0300) for per 1-point increase of SCUBE3 expression.ConclusionsThese findings demonstrate that the high expression of SCUBE3 indicates poor prognosis in breast cancer. SCUBE3 expression may serve as a potential diagnostic indicator of breast cancer.

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is more commonly associated with young patients, featuring high histological grade, visceral metastasis, and distant recurrence. Follistatin (FST) is a secreted extracellular regulatory protein that antagonizes TGF-β superfamily such as activin and TGF-β related superfamily such as bone morphogenetic protein (BMP). The implication of FST in the proliferation, angiogenesis, and metastasis of solid tumors documents good or poor outcome of patients with BC. However, the role of FST in TNBC remains unclear.MethodsData of 935 patients with breast cancer (BC) were extracted from TCGA. Case–control study, Kaplan–Meier, uni-multivariate COX, and ROC curve were utilized to investigate the relationship between FST expression and the clinical characteristics and prognosis of BC. Functional studies were used to analyze the effect of FST expression on proliferation, apoptosis, migration, and invasion of TNBC cell lines. Bioinformatic methods such as volcanoplot, GO annd KEGG enrichment, and protein–protein interactions (PPI) analyses were conducted to further confirm the different roles of FST in the apoptotic pathways among mesenchymal and mesenchymal stem-like cells of TNBC.ResultsData from TCGA showed that low FST expression correlated with poor prognosis (for univariate analysis, HR = 0.47, 95% CI: 0.27–0.82, p = 0.008; for multivariate analysis, HR = 0.40, 95% CI: 0.21–0.75, p = 0.004). Low FST expression provided high predicted value of poor prognosis in TNBC amongst BCs. FST knockdown promoted the proliferation, migration and invasion of BT549 and HS578T cell lines. FST inhibited the apoptosis of mesenchymal cells by targeting BMP7.ConclusionsLow FST expression is associated with poor prognosis of patients with TNBC. FST expressions exhibit the anisotropic roles of apoptosis between mesenchymal and mesenchymal stem-like cells but promote the proliferation, migration, invasion in both of two subtypes of TNBC in vitro. FST may be a subtype-heterogeneous biomarker for monitoring the progress of TNBC.

Bone marrow cells are differentiated into MDSCs by BCC-Ex through down-regulating the expression of CXCR4 and activating STAT3 signalling pathway.

Studies showed that the increase of myeloid‐derived suppressor cells (MDSCs) in tumour microenvironment is closely related to the resistant treatment and poor prognosis of metastatic breast cancer. However, the effect of tumour‐derived exosomes on MDSCs and its mechanism are not clear. Here, we reported that breast cancer cells (4T1)‐secreted exosomes (BCC‐Ex) were able to differentiate bone marrow cells into MDSCs and significantly inhibited the proliferation of T lymphocytes to provide an immunosuppressive microenvironment for cancer cells in vivo and in vitro. The number of MDSCs in bone marrow and spleen of 4T1 tumour‐bearing mice and BCC‐Ex infused mice was significantly higher than that of normal mice, whereas the number of T lymphocytes in spleen was significantly decreased. In addition, BCC‐Ex markedly promoted the differentiation of MDSCs from bone marrow cells or bone marrow cells derived macrophages, seen as the increased expressions of MDSCs‐related functional proteins Arginase‐1 (Arg‐1) and inducible nitric oxide synthase (iNOS). Furthermore, BCC‐Ex significantly down‐regulated the expressions of chemokine receptor CXCR4 and markedly up‐regulated the levels of inflammatory cytokines IL‐6 and IL‐10 in bone marrow cells and macrophages and remarkably inhibited the division and proliferation of T cells. Importantly, CXCR4 agonist, CXCL12, could reverse the function of BCC‐Ex, indicating that BCC‐Ex‐induced MDSCs might be dependent on the down‐regulation of CXCR4. Western blot showed that BCC‐Ex significantly promoted the phosphorylation of STAT3 in bone marrow cells, resulting in the inhibitions of the proliferation and apoptosis of bone marrow cells, and the aggravation of the differentiation of bone marrow cells into MDSCs.

Evaluation of circulating tumor cells as a prognostic biomarker for early recurrence in stage II-III breast cancer patients using CytoSorter® system: a retrospective study.

PurposeCirculating tumor cells (CTCs) are known to be associated with late recurrence and poor prognosis in breast cancer (BC). Different CTC enrichment platforms have different CTC cut-off values for poor prognosis. This study aimed to evaluate whether preoperative CTCs could be a prognostic factor for early recurrence of disease in BC patients with resectable tumors, and to ascertain the CTC cut-off value for early recurrence with CytoSorter® CTC system.MethodsThirty-six stage II and III BC patients who had preoperative (pre-op) CTC detection and underwent a mastectomy or lumpectomy for curative intent between January and May 2018 were enrolled in this retrospective study. CTC detection was performed using CytoSorter® CTC system. Correlations of patients’ demographics, clinicopathological characteristics, adjuvant therapies and CTCs with relapse and survival were evaluated.ResultsCTCs were detected in 32 out of 36 patients before surgery. Nine patients developed relapses during follow-up, and seven of them were distant recurrence. Univariate analysis showed that CTCs were correlated with two-year recurrence free survival (RFS) and distant RFS (D-RFS) (P = 0.013 and 0.029, respectively). Two-year RFS and D-RFS were 85.2% and 88.9%, respectively, for patients with <4 CTCs, while 44.4% and 55.6%, respectively, for patients with ≧4 CTCs. In multivariate analysis, only CTC was shown to be correlated with two-year RFS (HR: 0.219, 95% CI: [0.058–0.82], P = 0.024) and D-RFS (HR: 0.218, 95% CI [0.048–0.977], P = 0.047).ConclusionBC patients with pre-op CTCs ≥4 per four mL of blood have significantly reduced two-year RFS and D-RFS. A pre-op CTC cut-off of four per four mL of blood was found for CytoSorter® to identify BC patients with a higher risk for early recurrence.

A two-miRNA signature of upregulated miR-185-5p and miR-362-5p as a blood biomarker for breast cancer

BackgroundDifferentially expressed microRNAs (miRNAs) in the blood of breast cancer patients may serve as diagnostic biomarkers. MethodsIn this study, miRNA microarray of the blood of breast cancer patients and healthy controls was performed. Candidate differentially expressed miRNAs were further verified by real-time polymerase chain reaction in 68 breast cancer patients and 13 healthy controls. ResultsSix upregulated blood miRNAs (miR-26b-5p, miR-106b-5p, miR-142-3p, miR-142-5p, miR-185-5p, and miR-362-5p) were identified in breast cancer patients. These six miRNAs could discriminate breast cancer patients from healthy controls, with areas under the receiver operating characteristic curve (AUCs) of 0.8891, 0.8158, 0.8529, 0.8507, 0.9050, and 0.9333, respectively. Bioinformatic analysis showed that the six miRNAs were potentially involved in numerous cancer-related pathways, including the mitogen-activated protein kinase signaling pathway, nuclear factor-kappa B signaling pathway, and the transforming growth factor-beta signaling pathway. Importantly, two miRNAs (miR-185-5p and miR-362-5p) were used to construct a two-miRNA panel by logistic regression. The two-miRNA panel displayed a better diagnostic performance than each of the miRNAs alone, with a higher AUC (0.957), sensitivity (92.65 %), and specificity (92.31 %). Additionally, the high expression of the six miRNAs or the two-miRNA panel was associated with poor prognosis of breast cancer. ConclusionsWe identified six upregulated miRNAs and a two-miRNA panel in the blood as potential biomarkers for the diagnosis and prognosis of breast cancer.

Research on the effect of interfering with miRNA-155 on triple-negative breast cancer cells.

Triple negative breast cancer (TNBC) is a poor prognosis breast cancer with the highest mutation rate and limited treatment options. MiR-155 is highly expressed in TNBC, but its role and potential mechanism in TNBC remain to be elucidated. The aim of this study is to examine the effect of interfering with miRNA-155 on the inflammatory pathway of NLRP 3 in TNBC (MDA-MB-231). MiRNA-155-specific interference (Si-miR-155) on MDA-MB-231 cell was manifested by transfection of miRNA-155 inhibitor. Meanwhile, blank control (Blank) and negative control (NC) were set. Cell growth and proliferation rate were detected by MTT; apoptosis rate were detected by flow cytometry; colony forming test was used to detected cell viability; cell migration ability was detected by Wound healing assay; TNF-α, IL-18, IL-6 and IL-1β levels were detected by ELISA. The mRNA of miRNA-155, NLRP3, ASC, caspase-1 and Ki67 were detected by qRT-PCR. The expression levels of NLRP3, caspase-1, ASC and Ki67 were detected by Western blotting. The proliferation rate of Si-miRNA-155 group decreased, while the apoptosis rate increased significantly. After interfering with miRNA-155, the number of cancer cell colonies and the migration ability was decreased, and the secretion levels of IL-18, TNF-α, IL-6 and IL-1β were also inhibited. Moreover the mRNA and protein expression of NLRP3, caspase-1, ASC and Ki67 were significantly suppressed. Interference with miRNA-155 can inhibit the NLRP3 pathway of MDA-MB-231 cells, as well as the proliferation, migration and inflammatory factor secretion of MDA-MB-231 cell, and can accelerate its apoptosis.

Long Non-Coding RNA LINC00467 Correlates to Poor Prognosis and Aggressiveness of Breast Cancer.

Breast cancer remains the leading cause of female cancer-related mortalities worldwide. Long non-coding RNAs (LncRNAs) have been increasingly reported to play pivotal roles in tumorigenesis and cancer progression. Herein, we focused on LINC00467, which has never been studied in breast cancer. Silence of LINC00467 suppressed proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of breast cancer cells in vitro, whereas forced expression of LINC00467 exhibited the opposite effects. Furthermore, we demonstrated overexpression of LINC00467 promoted tumor growth, while knockdown of LINC00467 inhibited pulmonary metastasis in vivo. Mechanistically, LINC00467 down-regulated miR-138-5p by acting as a miRNA “sponge”. Besides, LINC00467 also up-regulated the protein level of lin-28 homolog B (LIN28B) via a direct interaction. A higher expression level of LINC00467 was observed in breast cancer tissues as compared to the adjacent normal counterparts and elevated LINC00467 predicted poor overall survival. Our findings suggest LINC00467 promotes progression of breast cancer through interacting with miR-138-5p and LIN28B directly. LINC00467 may serve as a potential candidate for the diagnosis and treatment of breast cancer.