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Background Mucinous breast carcinoma (MBC) is a relatively rare pathological type of breast cancer. Compared with mastectomy in MBC, the effect and safety of breast‐conserving therapy (BCT) remains unclear. Therefore, we investigated the long‐term prognosis of BCT and mastectomy in T1‐2 stage mucinous breast carcinoma via the Surveillance, Epidemiology, and End Results (SEER) database. Methods Totally, 8830 patients who were diagnosed of mucinous breast carcinoma between 2004 and 2014 from SEER database were reviewed retrospectively. Cox proportional hazards model and Kaplan‐Meier method were performed for evaluating the relationship between surgical method and prognosis. Results One thousand three hundred and twenty (14.9%) patients underwent mastectomy and 7510 (85.1%) underwent BCT. The median follow‐up time was 77 months. There were more non‐Hispanic white, married, and younger ( .05).While for patients who received BCT, the use of radiotherapy showed OS benefit. Conclusions This large population‐based study indicated patients who received BCT had better prognosis than those received mastectomy in T1‐2 stage MBC, especially in patients at the age of 50‐79 years. The use of radiotherapy showed OS benefit in patients receiving BCT. Breast‐conserving therapy might be preferred over mastectomy especially in locoregional treatment of T1‐2 stage MBC., This large population‐based study confirmed that patients with BCT had better prognosis than those with mastectomy in T1‐2 stage MBC, especially in patients with age of 50‐79 years. The use of radiotherapy show OS benefit in patients receiving BCT. Breast conserving therapy should be preferred over mastectomy in locoregional treatment of T1‐2 stage MBC.

Our study aims to construct a prognosis-related immune phenotype classifier for predicting clinical prognosis and immune activity in triple-negative breast cancer (TNBC). A total of 237 patients with TNBC from Sun Yat-sen University Cancer Center (SYSUCC) and 533 patients with TNBC from public datasets were included in our study. A stromal immune quantified index was generated with a LASSO Cox regression model based on five prognosis-related immune cells evaluated by CIBERSORT or IHC and was used to determine immune phenotypes. Immune features were evaluated in the samples before chemotherapy. A total of 119 patients in the SYSUCC training cohort were classified into immune Phenotypes A and B according to the density of stromal CD4+ T cells, γδ T cells, monocytes, M1 macrophages and M2 macrophages. Phenotype A predicted better survival than Phenotype B, and the classification was further validated in the testing cohort of 118 patients and the validation cohort of 533 patients. In the combined cohort, significant differences were found in Phenotype A compared to Phenotype B for the 5-year overall survival (83.5% vs 65.8%, respectively, P < .01) and the 5-year disease-free survival (87.3% vs 76.0%, respectively, P < .01). In Phenotype A, immune-related pathways were significantly enriched, and a higher level of immune checkpoint molecules, including PD-L1, PD-1 and CTLA-4, could be observed. The immune phenotype classification was an independent prognostic indicator for TNBC and might serve as a potential predictor for immune activity within the tumor microenvironment.

Melatonin has been recognized to slow breast cancer growth. The molecular mechanisms may involve long non-coding RNAs (lncRNAs). However, little is known on how melatonin affects lncRNA expression and function in breast cancer. We used microarrays to explore the expression profile of mRNAs and lncRNAs in melatonin-treated breast cancer cells. Kyoto encyclopedia of genes and genomes (KEGG) and Reactome pathways analysis were performed to identify the signaling pathways affected by altered expressed mRNAs after melatonin treatment. To explore the functions and mechanisms of the selected differentially expressed mRNA and lncRNA in breast cancer, we performed a series of experiments. We found that FK506-binding protein 3 (FKBP3) and lnc010561 were downregulated in melatonin-treated breast cancer cells. Knockdown of FKBP3 and lnc010561 inhibited breast cancer proliferation and invasion, and induced apoptosis. Also, lnc010561 and FKBP3 functioned as competing endogenous RNAs (ceRNAs) for miR-30. Our findings suggested that melatonin regulated breast cancer progression by the lnc010561/miR-30/FKBP3 axis. Melatonin may, therefore, function as an anticancer strategy for breast cancer.

Background: CDK12 is a promising therapeutic target in breast cancer with an effective ability of maintaining cancer cell stemness. Objective: We aim to investigate the mechanism of CDK12 in maintaining breast cancer stemness. Methods: CDK12 expression level was accessed by using RT-qPCR and IHC. CDK12-altered breast cancer cell lines MDA-MB-231-shCDK12 and SkBr-3-CDK12 were then established. CCK8, colony formation assays, and xenograft model were used to value the effect of CDK12 on tumorigenicity. Transwell assay, mammosphere formation, FACS, and lung metastasis model in vivo were determined. Western blot further characterized the mechanism of CDK12 in breast cancer stemness through the c-myc/β-catenin pathway. Results: Our results showed a higher level of CDK12 exhibited in breast cancer samples. Tumor formation, cancer cell mobility, spheroid forming, and the epithelial-mesenchymal transition will be enhanced in the CDK12high group. In addition, CDK12 was associated with lung metastasis and maintained breast cancer cell stemness. CDK12high cancer cells presented higher tumorigenicity and a population of CD44+ subset compared with CDK12low cells. Our study demonstrated c-myc positively expressed with CDK12. The c-myc/β-catenin signaling was activated by CDK12, which is a potential mechanism to initiate breast cancer stem cell renewal and may serve as a potential biomarker of breast cancer prognosis. Conclusion: CDK12 overexpression promotes breast cancer tumorigenesis and maintains the stemness of breast cancer by activating c-myc/β-catenin signaling. Inhibiting CDK12 expression may become a potential therapy for breast cancer.

Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.

Background Breast cancer and hepatitis B virus (HBV) infection are serious public health issues in China. But the effect of HBV infection on breast cancer remains unclear. The objective was to assess whether HBV infection was associated with prognosis of breast cancer. Methods A retrospective database of 1,924 invasive breast cancer patients from Sun Yat-sen University Cancer Center from 2008 to 2010 was established. Propensity score matching method was applied to balance baseline parameters. Logistic regression was used for identifying the independent risk factors of liver metastasis. Prognostic outcomes were evaluated via Kaplan-Meier analysis and Cox model. Results Primary evaluation of gross data suggested HBV infection was associated with much higher rate of liver metastasis. 642 patients were matched for analysis. The median follow-up time was about 69 months. Patients with HBV surface antigen (HBsAg) (+) had a specially higher risk of liver metastasis aside of other distant organs than those with HBsAg (−). HBsAg (−/+) was identified to be an independent risk factor of liver metastasis [odds ratio (OR), 2.651; 95% confidence intervals (CI), 1.213–5.796; P=0.015]. HBsAg (+) was associated with liver metastasis significantly in stage III or in estrogen receptor (ER) (+) and/or progesterone receptor (PR) (+), human epidermal growth factor receptor-2 (HER-2) (−) subtype. Meanwhile, patients with HBsAg (+) had significant shorter liver metastasis-free survival (LMFS) compared with HBsAg (−) patients (P=0.041). But the difference of overall survival (OS) between the HBsAg (−) and HBsAg (+) groups reached statistically no significance (P=0.425). The multivariate analysis suggested HBsAg (+) could worsen the outcome of LMFS [hazards ratio (HR), 2.450; 95% CI, 1.169–5.135; P=0.018]. Conclusions In breast cancer, HBsAg (+) was associated with specially a higher rate of liver metastasis and thus worsened the LMFS. HBsAg (−/+) was an independent risk factor of liver metastasis.

Background: There is increasing evidence that circular RNAs (circRNAs) participate in regulating cancer progression. However, the function and potential molecular mechanisms of circRNA in triple negative breast cancer (TNBC) are currently largely unclear. Results: We found that circAHNAK1 was significantly down-regulated in TNBC, and its expression was negatively associated with RFS and OS. Overexpression of circAHNAK1 can inhibit TNBC proliferation, migration and invasion in vitro. In vivo studies confirmed that circAHNAK1 inhibited TNBC tumor growth and metastasis. Mechanistic analysis indicated that circAHNAK1 acted as a miR-421 ceRNA (competitive endogenous RNA) to attenuate the inhibitory effect of miR-421 on its target gene RASA1. Conclusions: In conclusion, CircAHNAK1 inhibits proliferation and metastasis of TNBC by modulating miR-421 and RASA1. Methods: CircRNA microarrays were used to screen for differential circRNA expression profiles. qRT-PCR was used to detect the expression levels of circRNAs. The effect of circAHNAK1 on recurrence -free survival (RFS) and overall survival (OS) in patients with TNBC was subsequently analyzed. The role of circAHNKA1 in the progression of TNBC was further evaluated by multiple in vivo and in vitro assays. Finally, we focused on the regulation of circAHNAK1 on miR-421 and its targeted gene RASA1 in TNBC.

Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The adenosine 5’-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR—two compounds that mimic fasting—elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.

Background: Long non-coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non-coding RNA01638 (linc01638) in breast cancer, especially in HER2-positive breast cancer, remains largely unknown. Objective: To investigate the effect of linc01638 on tumorigenesis in HER2-positive breast cancer. Methods: We first used qRT-PCR to detect linc01638 expression in HER2-positive breast cancer cells and tissues. Then we analyzed the effects of linc01638 expression in HER2-positive breast cancer cells through cell apoptosis assay, cell proliferation assay, colony formation assay, and cell invasion assay. We conducted mouse xenograft model to further confirm the role of linc01638 in HER2-positive breast cancer. Moreover, we used Western blot and IHC analysis to access the effect of linc01638 on DNMTs, BRCA1 and PTEN expressions in transplanted tumors. Results: Linc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and invasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b, and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models. Linc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer.

Metastasis‐related mRNAs have showed great promise as prognostic biomarkers in various types of cancers. Therefore, we attempted to develop a metastasis‐associated gene signature to enhance prognostic prediction of breast cancer (BC) based on gene expression profiling. We firstly screened and identified 56 differentially expressed mRNAs by analysing BC tumour tissues with and without metastasis in the discovery cohort (GSE102484, n = 683). We then found 26 of these differentially expressed genes were associated with metastasis‐free survival (MFS) in the training set (GSE20685, n = 319). A metastasis‐associated gene signature built using a LASSO Cox regression model, which consisted of four mRNAs, can classify patients into high‐ and low‐risk groups in the training cohort. Patients with high‐risk scores in the training cohort had shorter MFS (hazard ratio [HR] 3.89, 95% CI 2.53‐5.98; P

BackgroundThere were no predictive prognosis factors of serum in male breast cancer, while breast cancer is a heterogeneous disease. The purpose of our study was to determine the prognostic implications of the pretreatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) in the serum of patients with male breast cancer. Methods：We retrospectively identified an random cohort of male breast cancer patients treated at the Sun Yat-Sen University Cancer Center between Jan1, 1996 and Dec31, 2016. A number of 108 patients had a different inflammation markers recorded pre-operation. Survival status was retrieved from our cancer center registry and phone follow-up. Cox proportional hazards regression model were used to analyze the disease-free survival (DFS) and overall survival (OS). Results：Among these patients in this study, 13 (12%) had disease recurrence, and 7 (6.5%) patients appeared distant metastasis. No statistically significant association of the preoperative NLR, PLR or LMR level with patients’ different outcomes was found. Conclusions: In short, we were unable to establish a connection between preoperative inflammation biomarkers and male breast cancer patients’ survival. Neither NLR, PLR nor LMR is useful for predicting prognosis in male breast cancer patients, and prospective studies to evaluate the above biomarkers as a simple prognostic trail is necessary.

BackgroundResidual cancer cells remaining after chemotherapy may have more aggressive behavior that promotes recurrence or metastasis, and which patients would benefit from subsequent additional treatment is controversial. The purpose of our study was to evaluate the prognostic value of the preoperative radiomics features of computed tomography (CT) imaging in breast cancer (BC) patients with residual tumors after neoadjuvant chemotherapy (NAC).MethodsPost-NAC CT images were reviewed from 114 patients who had received breast surgery and had residual breast tumors. The association of the 110 radiomics features derived from CT images with 5-year disease-free survival (DFS) was assessed by log-rank test in the training cohort, resulting in 13 prognostic radiomics features.ResultsWe constructed a radiomics signature consisting of four selected features by using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, which performed well in the discrimination with an area under the curve (AUC) of 0.78 (95% CI, 0.67–0.89) and 0.73 (95% CI, 0.59–0.87) in the training and validation cohorts, respectively. Radiomics nomogram, incorporating the radiomics signature with the conventional clinical variables, also performed well in the two cohorts (training cohort: AUC, 0.84; validation cohort: AUC, 0.82). Moreover, we found that the high-risk patients determined by our radiomics nomogram could benefit from postoperative adjuvant chemotherapy, while the low-risk and total patient groups could not.ConclusionsOur novel radiomics nomogram is a promising and favorable prognostic biomarker for preoperatively predicting survival outcomes and may aid in clinical decision-making in BC patients with residual tumors after NAC.

Background: Obesity has been reported to be a risk factor for breast cancer, but how obesity affects BC is unclear. Although BMI is the most commonly used marker for obesity, it is insufficient to evaluate the obesity-related pathophysiological changes in breast tissue. The purpose of this study was to establish a DNA-methylation-based biomarker for obesity and to explore the association of obesity with BC. Methods: Lasso regression was used to developed DNA-methylation-based BMI index (DM-BMI). Linear regression and paired t-test were used to assess the accuracy of DM-BMI in BMI prediction. A deconvolution algorithm based on DNA methylation data was used to calculate the proportion of adipose cell in tissues. The Estimate and Cibersort algorithm were used to assess the degree of tumor-infiltrating immune cells.Results: Using DNA methylation data from TCGA and GEO, we developed DM-BMI to evaluate the degree of obesity in breast tissues. In tissues from non-BC and BC population, the DM-BMI model exhibited high accuracy in BMI prediction. In BC tissues, DM-BMI correlated with increased adipose tissue content and BC tissues with increased DM-BMI exhibited higher expression of pro-inflammatory adipokines. Next, we identified the gene expression profile relating to DM-BMI. Using GO and KEGG database, we observed that the DM-BMI-related genes mostly involve in the process of cancer immunity. DM-BMI is positively correlated with T cell infiltration in BC tissues. Further, we observed that DM-BMI positively correlated with immune checkpoint inhibitors [1] response markers in BC. Conclusions: Collectively, we developed a new biomarker for obesity and discovered that BC tissues from obese individuals exhibit an increased degree of immune cell infiltration indicating that obese BC patients might be the potential beneficiaries for ICI treatment.

Background For primary neuroendocrine carcinoma of breast was a very rare subtype in breast cancers, its prognosis was still controversial and there was no independent standard for its treatment. The purpose of our retrospective study was to construct a nomogram to predict the overall survival (OS) of patients with neuroendocrine carcinoma of the breast. Methods 150 patients of training cohort were collected from Surveillance, Epidemiology, and End Results (SEER) database diagnosed between 2003 and 2015, and 93 patients of verification cohort were enrolled from Sun Yat-sen University Cancer Center (Guangzhou, China) diagnosed between 2004 and 2018. The nomogram was constructed uniting three significantly risk factors of overall survival identified by univariate and multivariate analysis and then validated using receiver operating characteristic (ROC) curves for discrimination, calibration plots and the decision curves analysis (DCA). Results Age, N stage and PR status were closely and significantly related to overall survival in patients with breast neuroendocrine carcinoma. The C-index of nomogram in the training and verification cohorts are 0.775 (95% CI, 0.784 to 0.615) and 0.760 (95% CI, 0.705 to 0.800) respectively. Calibration plots of practical and predicted possibility for the nomogram demonstrated that the predictive 5-year overall survival rate was in accordance with the actual overall survival probability in both sets. Moreover, the decision curves (DCA) also expressed pretty clinical benefit of the nomogram across a range of high-risk threshold. Conclusion This novel population-based nomogram may help with treatment decisions in patients with neuroendocrine carcinoma of the breast (NEBC).

The prognosis of breast cancer brain metastasis (BCBM) is extremely poor due to its resistance to conventional therapy. Elucidation of the molecular mechanisms of BCBM could contribute to the development of new therapeutic targets. In this study, we isolated RNA samples from primary breast cancer or BCBM, and then performed mRNA profiling. We determined that SOX2 is associated with the occurrence of BCBM and could be a predictor of BCBM. High levels of SOX2 were significantly associated with decreasing BCBM-free survival in patients. Overexpression of SOX2 in breast cancer cells enhanced cancer cell adhesion to brain microvascular endothelial cells, transendothelial migration, and in vitro blood-brain barrier (BBB) migration, whereas silencing SOX2 inhibited these events. SOX2 can increase cancer cell migration and BBB permeability by upregulating FSCN1 and HBEGF, thereby promoting BBB migration of breast cancer cells. Moreover, high levels of FSCN1 and HBEGF were significantly associated with reducing BCBM-free survival in breast cancer patients. Further study indicated that SOX2 mediates the expression of HBEGF and FSCN1 by activating AKT and β-catenin signaling pathways. Additionally, in vivo experiments showed that SOX2 promotes the development of BCBM. This study demonstrated that SOX2 promotes BCBM by upregulating the expression of FSCN1 and HBEGF., Graphical Abstract, Xiao et al. identify that SOX2 is associated with the occurrence of breast cancer brain metastasis after microarray screening and extended sample validation. They demonstrate that SOX2 upregulates the expression of HBEGF and FSCN1 by activating the β-catenin and AKT signaling pathways, which together promote breast cancer brain metastasis.

Objective The impact of primary tumor resection (PTR) on survival is still controversial in stage IV breast cancer. This systematic review and meta-analysis aimed to evaluate the impact of PTR on overall survival (OS) in stage IV breast cancer. Methods Comprehensive literature search was conducted to identify studies comparing PTR with no PTR for stage IV breast cancer. The quality of the studies was assessed using Cochrane risk of bias tool and Newcastle-Ottawa Scale. We used subgroup and meta-regression analysis to assess the contribution of demographic and clinical factors to heterogeneity. Results Data on 714 patients in 3 randomized controlled trials (RCTs) and 67,272 patients in 30 observational studies were included. One RCT was terminated early due to poor recruitment, and the remaining two RCTs’ design were different, thus RCTs were only performed systematic review without meta-analysis. The pooled outcomes of 30 observational studies showed PTR significantly improved OS (HR = 0.65; 95%CI, 0.61 to 0.70, P Conclusions PTR should not be part of routine clinical practice in stage IV breast cancer but might be performed in selected patients. Our findings highlight PTR might be valuable in patients with limited disease burden or attaining clear margin.

Background Resection of the primary tumor is recommended for symptom relief in de novo stage IV breast cancer. We explored whether local surgery could provide a survival benefit in these patients and attempted to characterize the population that could benefit from surgery. Methods Metastatic Breast cancer patients (N = 313) with intact primary tumor between January 2006 and April 2013 were separated into two groups according to whether or not they had undergone surgery. The difference in characteristics between the two groups was analyzed using chi-square test, Fisher’s exact test and Mann-Whitney test. Univariable and multivariable Cox regression and stratified survival analysis were used to assess the effect of surgery on survival. Results Of the 313 patients, 188 (60.1%) underwent local surgery. Patients with local surgery had a 47% reduction in mortality risk vs. those with no surgery (median survival 78 months vs. 37 months; HR = 0.53; 95% CI, 0.36–0.78) after adjustment for clinical and tumor characteristics. Stratified survival analysis showed that patients with bone metastasis alone (and primary tumor ≤5 cm), soft tissue metastasis, or ≤ 3 metastasis sites benefit from surgery. Conclusion Surgical resection of the primary tumor can improve survival in selected de novo stage IV breast cancer patients.

Background Invasive micropapillary carcinoma (IMPC) is a rare histological subtype of breast cancer. The outcome of IMPC remains controversial; we conducted a meta-analysis of propensity score matching (PSM) studies to evaluate the prognostic difference between IMPC and invasive ductal carcinoma (IDC). Methods We searched PubMed, EMBASE and the Cochrane library for PSM studies comparing survival data between IMPC and IDC. The summarized odds ratios (ORs) and 95% confidence interval (95% CI) are calculated by STATA software utilizing fixed-effect or random-effect models, depending on the heterogeneity of the eligible studies. Results Eight PSM studies including 2102 IMPC patients are included in the meta-analysis. Compared with IDC, IMPC has a similar overall survival (OS) (estimated OR = 0.87, 95% CI: 0.61–1.25), but a shorter relapse free survival (RFS) (estimated OR = 1.31, 95% CI: 1.06–1.61); the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC (estimated OR = 3.60, 95% CI: 1.99–6.52). Funnel plots and Egger’s tests are used to evaluate publication bias and the p value for OS and RFS are 0.036 and 0.564 respectively. Conclusions Our results demonstrate that compared with IDC, IMPC exhibits a similar, even favorite OS, but a shorter RFS; and the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC. These results could contribute to the individualized therapy and follow-up strategies for IMPC patients., Highlights • This is the first meta-analysis of PSM studies concerning on prognosis of IMPC, with the largest sample until now. • Compared with IDC, IMPC exhibits a similar, even favorite OS, but a shorter RFS; and the shorter RFS might owe to the significantly higher loco-regional recurrence rate.

Background: Numerous studies have showed that internal mammary lymph node (IMLN) metastasis is an important adverse prognostic factor in patients with breast cancer (BC), however, there are no available prediction model for the preoperative diagnosis of IMLN metastasis. Methods: Data from 102 breast cancer patients treated with IMLN operation were used to establish and calibrate a nomogram for IMLN status based on multivariate logistic regression. Prediction performance of this model was further validated with a second set of 50 patients with BC. Discrimination of the predict model was assessed by the C-index, and calibration assessed by calibration plots. Moreover, we conducted the decision curve analysis (DCA) to evaluate the clinical value of the nomogram. Finally, the survival status of patients in different risk groups based on nomogram were also compared. Results: The final multivariate regression model included tumor location, lymph vascular invasion (LVI), and pathological axillary lymph node stage (pALN stage). A nomogram was developed as a graphical representation of the model and had good calibration and discrimination in both sets (with C-index of 0.86 and 0.83 for the training and validation set, respectively). Moreover, the DCA showed the clinical usefulness of our constructed nomogram. False negative (FN) in low risk group classified by nomogram (FN-LR-nomogram) did not significantly impact adjuvant treatment decision making, and more importantly, patients with FN-LR-nomogram had recurrence-free survival equivalent to patients with pathologically ture negative in low risk group classified by nomogram (TN-LR-nomogram). Conclusions: As a non-invasive prediction tool, our nomogram shows favorable predictive accuracy for IMLN metastasis in patients with BC and can serve as a basis to integrate future molecular markers for its clinical application.

Long non-coding RNAs (lncRNAs) are reported to play vital roles in the progress of multiple cancers. However, the functions of lncRNAs in breast cancer remain to be discovered. We performed microarrays to identify the differentially expressed mRNAs and lncRNAs in breast tissues with or without miR-34a knockout. To explore the functions of the differentially expressed mRNA and lncRNA in breast cancer, we conducted a series of experiments. We found that Adam12 and lnc015192 were significantly upregulated in miR-34a knockout breast tissues. Knockdown of Adam12 and lnc015192 inhibited breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Further experiments revealed that lnc015192 regulated Adam12 expression by functioning as a competing endogenous RNA (ceRNA) for miR-34a. In summary, our study demonstrate that Adam12 and lnc015192 promote breast cancer metastasis partly by sponging miR-34a through the ceRNA mechanism.

Background: It has been reported that diallyl disulfide (DADS) has anti-proliferative activity in many cancers. Objective: The purpose of this study was to investigate the functions of DADS and the underlying mechanisms of its effect in breast cancer stem cells (BCSCs). Method: Mammosphere formation assay, glucose consumption assay, lactate production assay and mouse xenograft experiments were performed to explore the functions of DADS in BCSCs. ATPase activity assay, western blotting and immunohistochemistry (IHC) assay were conduct to explore the mechanisms underlying the effects of DADS in BCSCs. Results: The results showed that DADS suppressed cell stemness and glucose metabolism in BCSCs. In vivo mouse xenograft experiments showed that DADS inhibited the proliferation and metastasis of BCSCs. Then, we continued to explore the mechanisms underlying the effects of DADS in BCSCs and found that DADS acts by targeting CD44, Pyruvate kinase M2 (PKM2) and AMP-activated protein kinase (AMPK) signaling pathways. IHC analysis of 125 breast cancer patients’ tissues demonstrated that CD44, PKM2 and AMPK expression levels were positively correlated. In addition, positive CD44, PKM2 and AMPK expression was associated with poor patient overall survival (OS) and disease-free survival (DFS). Conclusion: In summary, DADS suppresses cell stemness, proliferation, metastasis and glucose metabolism in BCSCs partly through the inhibition of CD44/PKM2/AMPK. DADS may be used as a potential therapy for breast cancer treatment.

The risk factors for morbidity and mortality in breast cancer lung metastases (BCLM) patients still remain poorly identified. The aim of this study was to assess the incidence and survival of BCLM and associated risk factors. Patients with BCLM were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression analysis was used to determine the risk factors for BCLM. Predictors of factors associated with death were analyzed in Cox regression and Fine and Gray's test. Of the 11568 patients with stage IV breast cancer, 4213 (36.4%) had BCLM and 1214 (10.5%) had metastases confined to lungs. The median survival time for patients with BCLM was 21 months, and 15.5% of the patients were alive more than 3 years. The tumor subtype distribution was 45.3% HR- /HER2- , 12.2% HR+ /HER2+ , 7.8% HR- /HER2+, and 15.0% triple-negative subtype. Compared with patients without BCLM, those with BCLM were more likely to be aged, female, black, higher tumor grade, HR- /HER2+ , HR+ /HER2+, and triple-negative subtypes at diagnosis. Survival analysis showed that the aged, black race, HR- /HER2+ , triple-negative subtype, higher grade were the independent risk factor for BCLM patients' survival, while HR+ /HER2+ subtype, insured status, and married status suggested better prognosis. In conclusion, the incidence and prognosis of BCLM varied by tumor subtypes, age, and race. Elderly patients with HER2-positive or triple-negative tumors were more likely to have BCLM.

More than half patients who undergo axillary lymph node (ALN) surgery are ALN negative in early-stage invasive breast cancer (EIBC). Thus, to avoid excessive treatment, we aim to establish and validate a novel nomogram model for the preoperative diagnosis of ALN status in patients with EIBC. In total, 864 patients with EIBC from two independent centers were enrolled in our study. For the discovery set, miRNAs expression profiling with functional roles in ALN metastasis was discovered by microarray analysis and validated by quantitative polymerase chain reaction (PCR). For the training and validation cohorts, we used PCR to quantify miRNAs expression in a model development cohort and assessed miRNAs signature in an internal validation cohort and external independent validation cohort. Multivariable logistic regression analyses were used to establish a nomogram model for the likelihood of ALN metastasis from miRNAs signature and clinical variables. A signature of nine-miRNA was significantly associated with ALN status. The predictive ability of our nomogram that included miRNAs signature and clinical-related variables (age, tumor size, tumor location and axillary ultrasound-reported ALN status) was significantly greater than a model that only considered clinical-related factors (concordance index: 0.856, 0.796) and also performed well in the two validation cohorts (concordance index: 0.841, 0.747). Our nomogram is a reliable prediction method that can be conveniently used to preoperatively predict ALN status in patients with EIBC. Therefore, after further confirmation in prospective and multicenter clinical trial, omission of axillary surgery may be feasible for some patients with EIBC in the future.

Background: CD44 and ALDH1 have been recognized as the most widely used markers to identify breast cancer stem cells (BCSCs). However, limited to tissue sample and rare population, BCSCs have always been not easily detected. We aimed to measure CD44 and ALDH1A1 (major contributor to ALDH1 activity) levels in serum and explore the prognostic value in primary breast cancer patients. Methods: This study included 140 primary breast cancer patients with stage I-III. Serum samples were collected before surgery and stored at -80 degrees. CD44 and ALDH1A1 were measured by chemiluminescent assay. Results: High serum CD44 levels (≥ 417.4 ng/mL) were correlated with postmenopausal status (P = 0.006), estrogen receptor negativity (P = 0.025), progesterone receptor negativity (P = 0.002) and adjuvant chemotherapy (P = 0.003). The mean serum CD44 levels of luminal group (406.4 ± 68.3 ng/mL) were significantly lower than triple negative group (506.8 ± 175.5 ng/mL) (P < 0.001). There was no correlation between serum ALDH1A1 levels and molecular subtypes. Multivariate analysis revealed that high serum CD44 level (≥ 417.4 ng/mL), was an independent factor for PFS (P = 0.019) and OS (P = 0.008). However, serum ALDH1A1 has no impact on either PFS (P = 0.613) or OS (P = 0.441). Conclusion: Serum CD44 was an independent prognostic indicator in primary breast cancer. However, serum ALDH1A1 has no impact on survivals and might not be an appropriate candidate to predict prognosis for breast cancer.

Purpose Survival of metastatic breast cancer (MBC) patient remains unknown and varies greatly from person to person. Thus, we aimed to construct a nomogram to quantify the survival probability of patients with MBC. Materials and Methods We had included 793 MBC patients and calculated trends of case fatality rate by Kaplan-Meier method and joinpoint regression. Six hundred thirty-four patients with MBC between January 2004 and July 2011 and 159 patients with MBC between August 2011 and July 2013 were assigned to training cohort and internal validation cohort, respectively. We constructed the nomogram based on the results of univariable and multivariable Cox regression analyses in the training cohort and validated the nomogram in the validation cohort. Concordance index and calibration curves were used to assess the effectiveness of nomogram. Results Case fatality rate of MBC was increasing (annual percentage change [APC], 21.6; 95% confidence interval [CI], 1.0 to 46.3; p < 0.05) in the first 18 months and then decreased (APC, -4.5; 95% CI, -8.2 to -0.7; p < 0.05). Metastasis-free interval, age, metastasis location, and hormone receptor status were independent prognostic factors and were included in the nomogram, which had a concordance index of 0.69 in the training cohort and 0.67 in the validation cohort. Calibration curves indicated good consistency between the two cohorts at 1 and 3 years. Conclusion In conclusion, the fatality risk of MBC was increasing and reached the summit between 13th and 18th month after the detection of MBC. We have developed and validated a nomogram to predict the 1- and 3-year survival probability in MBC.

// Weige Tan 1, 2, * , Wei Luo 1, * , Weijuan Jia 1 , Gehao Liang 1 , Xinhua Xie 3 , Wenbo Zheng 2 , Erwei Song 1, 4 , Fengxi Su 1 , Chang Gong 1 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 2 Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Chang Gong, email: changgong282@163.com Fengxi Su, email: fengxisu@vip.163.com Keywords: breast cancer, pathologic complete response, neoadjuvant chemotherapy, Nottingham prognostic index, IHC4 Received: July 13, 2016 Accepted: November 07, 2016 Published: November 24, 2016 ABSTRACT Pathologic complete response (pCR) prediction after neoadjuvant chemotherapy (NAC) is important for clinical decision-making in breast cancer. This study investigated the predictive value of Nottingham prognostic index (NPI), Immunohistochemical four (IHC4) score and a new predictive index combined with them in estrogen-positive (ER+) breast cancer following NAC. We retrospectively gathered clinical data of 739 ER+ breast cancer patients who received NAC from two cancer centers. We developed a new predictive biomarker named NPI+IHC4 to predict pCR in ER+ breast cancer in a training set (n=443) and validated it in an external validation set (n=296). The results showed that a lower IHC4 score, NPI and NPI+IHC4 were significantly associated a high pCR rate in the entire cohort. In the study set, NPI+IHC4 showed a better sensitivity and specificity for pCR prediction (AUC 0.699, 95% CI 0.626-0.772) than IHC4 score (AUC 0.613, 95% CI 0.533-0.692), NPI (AUC 0.576, 95% CI 0.494-0.659), tumor size (AUC 0.556, 95% CI 0.481-0.631) and TNM stage (AUC 0.521, 95% CI 0.442-0.601). In the validation set, NPI+IHC4 had a better predictive value for pCR (AUC 0.665, 95% CI 0.579-0.751) than IHC4 score or NPI alone. In addition, ER+ patients with lower IHC4, NPI and NPI+IHC4 scores had significantly better DFS in both study and validation sets. In summary, NPI+IHC4 can predict pCR following NAC and prognosis in ER+ breast cancer, which is cost-effect and potentially more useful in guiding decision-making regarding NAC in clinical practice. Further validation is needed in prospective clinical trials with larger cohorts of patients.

As a new rising star of non-coding RNA, circular RNAs (circRNAs) emerged as vital regulators with biological functions in diverse of cancers. However, the function and precise mechanism of the vast majority of circRNAs in triple-negative breast cancer (TNBC) occurrence and progression have not been clearly elucidated. In the current study, we identified and further investigated hsa_circ_0002453 (circRAD18) by analyzing our previous microarray profiling. Expression of circRAD18 was found significantly upregulated in TNBC compared with normal mammary tissues and cell lines. circRAD18 was positively correlated with T stage, clinical stage and pathological grade and was an independent risk factor for TNBC patients. We performed proliferation, colony formation, cell migration, apoptosis and mouse xenograft assays to verify the functions of circRAD18. Knockdown of circRAD18 significantly suppressed cell proliferation and migration, promoted cell apoptosis and inhibited tumor growth in functional and xenograft experiments. Through luciferase reporter assays, we confirmed that circRAD18 acts as a sponge of miR-208a and miR-3164 and promotes TNBC progression through upregulating IGF1 and FGF2 expression. Altogether, our research revealed the pivotal role of circRAD18-miR-208a/3164-IGF1/FGF2 axis in TNBC tumorigenesis and metastasis though the mechanism of competing endogenous RNAs. Thus, circRAD18 may serve as a novel prognostic biomarker and potential target for TNBC treatment in the future.

Immune system disorder is associated with metastasis of triple-negative breast cancers (TNBCs). A robust, individualized immune-related genes (IRGs)-based classifier was aimed to develop and validate in our study to precisely estimate the axillary lymph node (ALN) status preoperatively in patients with early-stage TNBC. We first analyzed RNA sequencing profiles in TNBC patients from The Cancer Genome Atlas database by using bioinformatics approaches, and screened 23 differentially expressed IRGs. A 9-gene panel was generated with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68–0.87]. We detected the 9 ALN-status-related IRGs in the training set (n = 133) and developed a reduced and optimized five-IRGs signature, which effectively distinguished TNBC patients with ALN metastasis (AUC, 0.80; 95% CI, 0.65–0.86), and was superior to preoperative ultrasound-based ALN status (AUC, 0.73; 95% CI, 0.53–0.93). Predictive efficiency (AUC, 0.77; 95% CI 0.61–0.93) of this five-IRGs signature was validated in the validation set (n = 81). Furthermore, IRGs nomogram incorporated IRGs signature with US-based ALN status showed higher ALN status prediction efficacy than US-based ALN status and five-IRGs signature alone in both training and validation sets. IRGs nomogram may aid in identifying patients who can be exempted from axillary surgery. Novelty and impact: An immune-related genes (IRGs) nomogram was first developed and externally validated in our study, which incorporated the IRGs signature with ultrasound (US)-based axillary lymph nodes (ALN) status. IRGs nomogram is superior to IRGs signature alone for preoperative estimation of ALN metastasis in patients with triple-negative breast cancer (TNBC). It is a favourable biomarker for preoperatively predicting ALN metastasis risk and may aid in clinical decision-making in early-stage TNBCs.

// Weige Tan 1, 5 , Xinhua Xie 2, 3, 5 , Laisheng Li 4, 5 , Hailin Tang 2, 3 , Xigang Ye 1 , Lun Chen 1 , Wei Tang 1 , Jin Gao 1 , Lingxiao Pan 1 , Xiaoshen Zhang 1 , Feng Ye 2, 3 , Xing Li 2, 3 , Lu Yang 2, 3 , Xiaoming Xie 2, 3 , Wenbo Zheng 1 1 Department of Breast Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China 2 Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China 3 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China 4 Department of Laboratory Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China 5 These authors contributed equally to this work Correspondence to: Wenbo Zheng, email: wenbo_zheng@163.com Xiaoming Xie, email: xiexm@sysucc.org.cn Keywords: MACC1, breast cancer, diagnosis, biomarker, serum Received: September 07, 2016 Accepted: October 14, 2016 Published: October 25, 2016 ABSTRACT Metastasis-associated in colon cancer-1 (MACC1) promotes colorectal cancer progression and predicts prognosis. The aim of our study was to determine the diagnostic and prognostic value of preoperative serum MACC1 levels in breast cancer patients. Serum MACC1 levels were measured in 378 breast cancer patients, 120 patients with benign breast disease, and 40 healthy volunteers using an ELISA. Serum MACC1 levels were higher in breast cancer patients than patients with benign disease or healthy volunteers. Increased serum MACC1 was associated with breast cancer TNM stage ( P < 0.001), tumor size ( P < 0.001), lymph node metastasis ( P < 0.001), and Ki-67 status ( P = 0.014). Serum MACC1 measurement successfully discriminated breast cancer patients from normal and healthy controls (AUC = 0.785, 95% CI: 0.746–0.825) with an optimal cut-off value of 38.35 pg/ml (sensitivity = 0.725, specificity = 0.696). Moreover, serum MACC1 exhibited significant prognostic value in breast cancer (AUC = 0.757, 95% CI: 0.700–0.814), and high MACC1 was associated with poor disease-free survival (HR 5.63, 95% CI: 3.51–9.04; P < 0.001). Our findings demonstrated that circulating MACC1 could serve as a reliable diagnostic and prognostic biomarker for breast cancer.

// Peng Liu 1, 2, * , Feng Ye 1, 2, * , Xinhua Xie 1, 2, * , Xing Li 1, 2 , Hailin Tang 1, 2 , Shuaijie Li 1, 2 , Xiaojia Huang 1, 2 , Cailu Song 1, 2 , Weidong Wei 1, 2 , Xiaoming Xie 1, 2 1 Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China 2 State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Xiaoming Xie, e-mail: xiexm@sysucc.org.cn Weidong Wei, e-mail: weiwd@sysucc.org.cn Keywords: mir-101-3p, AMPK, triple negative breast cancer, tumor metabolism Received: November 16, 2015 Accepted: March 28, 2016 Published: April 28, 2016 ABSTRACT mir-101-3p has been reported to be a tumor suppressor and a promising therapeutic target in cancer. Recently, AMPK dysfunction has been highlighted in cancers, including breast cancer. The aim of this study is to investigate the biological roles of mir-101-3p and AMPK in breast cancer. Our research demonstrated that AMPK was up-regulated in breast cancer tissues and cell lines, especially in triple negative breast cancer (TNBC). High-expression of AMPK correlated with poor outcome in both total breast cancer and TNBC patients. Ectopic expression of AMPK improved glucose uptake, glycolysis, proliferation of TNBC cells in vitro and its tumorigenicity in vivo. AMPK was predicted to be a direct target of mir-101-3p. The luciferase reporter assay was performed to certificate this prediction. The expression of AMPK was suppressed by transfection of mir-101-3p in TNBC cells. Over-expression of mir-101-3p or knock-down of AMPK inhibited glucose metabolism and proliferation of TNBC cells in vitro. Our study provides evidence that mir-101-3p- AMPK axis could be a promising therapeutic target in TNBC targeting tumor metabolism.

The molecular phenotype of circulating tumor cells is associated with clinical outcome of patients with breast cancer. The aim of this study was to enhance the prognostic accuracy of the circulating tumor cell phenotype in metastatic breast cancer by incorporating miRNA into a combined prediction model., Background. The molecular phenotype of circulating tumor cells (CTCs) was associated with clinical outcome of patients with breast cancer. CTCs isolated from patients with metastatic breast cancer (MBC) display a unique microRNA (miRNA) expression profile. The aim of this study was to enhance the prognostic accuracy of the CTC phenotype in patients with MBC, by incorporating miRNA into a combined prediction model. Subjects, Materials, and Methods. CTCs were detected by CellSearch and enriched by magnetic cell sorting. miRNA deep sequencing and quantitative polymerase chain reaction were used to screen and verify potentially CTC‐specific miRNA candidates. Patients with MBC were enrolled from two independent cohorts, and overall survival (OS) and chemotherapy response were analyzed. Results. We screened and identified that miR‐106b was an upregulated molecule in patients with MBC with CTC ≥5/7.5 mL (n = 16) compared with patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8). The expression of CTC‐specific miR‐106b correlated with vimentin and E‐cadherin in CTC and acted as an independent factor for predicting OS (hazard ratio 2.157, 95% confidence interval [CI] 1.098–4.239, p = .026). Although CTC‐specific miR‐106b, E‐cadherin, and vimentin showed a prognostic potential independently, the prognostic performance for OS based on the combination of three markers was significantly enhanced in Cohort 1 (area under the curve [AUC] 0.752, 95% CI 0.658–0.847, n = 128) and further validated in Cohort 2 (AUC 0.726, 95% CI 0.595–0.856, n = 91). Besides, a combined model incorporating miR‐106b was associated with therapy response. Conclusion. The phenotypic assemblies of CTC incorporating miR‐106b show enhanced prognostic accuracy of overall survival in patients with MBC. Implications for Practice. In order to enhance the prognostic accuracy of the circulating tumor cell (CTC) phenotype in patients with metastatic breast cancer (MBC), this study screened and identified a CTC‐specific microRNA (miRNA), miR‐106b, as an upregulated molecule based on the comparison of miRNA profile between CTCs, primary tumors, and healthy blood donors. By incorporating miR‐106b into a combined prediction model, the prognostic accuracy of the CTC phenotype for patients with MBC was greatly improved in both the training and validation cohorts. This work provides clinical evidence supporting the prognostic potential of CTC‐specific miRNA for patients with MBC. These results indicate that developing CTC‐specific miRNAs as new biomarkers will help to further optimize personalized therapy.

The molecular mechanisms underlying triple-negative breast cancer (TNBC) pathology are not fully understood. Here, we reviewed the SOX8 transcript level in 24 types of cancer and normal tissues and the SOX8 expression pattern in breast cancer from the TCGA and METABRIC data sets and found that SOX8 was highly expressed in TNBC. We investigated the effect of SOX8 on tumorigenicity, migration and apoptosis in TNBC cell lines and xenografts models. We identified SOX8 as a functional oncogene that involved in the maintenance of stem-like capacities in TNBC cells. Through a promoter truncation experiment and ChIP experiment, we verified zinc finger E-box binding homeobox 1 (ZEB1) as a transcriptional activator of SOX8 that enhanced SOX8 expression by binding to its promoter. We evaluated the ZEB1 and the SOX8 levels in 240 TNBC patients and high expression of ZEB1 and SOX8 were significantly associated with poor prognosis. We demonstrated the significance of the ZEB1–SOX8 axis in regulating TNBC cancer stem-like cells (CSCs) and its connection with poor prognosis. Due to its vital role in TNBC CSCs, the ZEB1–SOX8 regulatory axis could be a promising therapeutic target for TNBC.

Background: Little is known about the clinical features of breast cancer with synchronous hepatic metastases (BCSHM). In this retrospective study, we aimed to feature the incidence and survival outcome of BCSHM. Methods: Data from the 2016 SEER*Stat database (version 8.3.2) was used. The effect of patient and tumor characteristics on the odds of developing of BCSHM was analyzed. Survival was investigated using Kaplan-Meier and Cox regression analyses. A competing risk model was also applied to further investigate cancer-specific survival. Results: Of 240911 patients with breast cancer, we identified 3468 patients (1.44%) with BCSHM. Tumor subtypes distribution of BCSHM were 45.3% HR+/HER2-, 12.2% HR+/HER2+, 7.83% HR-/HER2+ and 15.0% triple-negative subtype. The median OS of the entire cohort was 14 months, and only about 13.5% of patients survived at 3 years. Median survival was significantly shorter in triple-negative cohort (8 months) and gradually increased in HR+/HER2- (19 months), HR-/HER2+ (22 months) and HR+/HER2+ (33 months) cohorts (P

The management of advanced nasopharyngeal carcinoma (NPC) remains a challenge. The ubiquitous nature of Epstein–Barr virus (EBV) infection in nonkeratinizing NPC has forced us to investigate novel drugs for NPC in the presence of EBV. In this study, we performed a small-scale screening of a library of compounds that target epigenetic regulators in paired EBV-positive and EBV-negative NPC cell lines. We found that bromodomain and extra-terminal (BET) inhibitor JQ1 preferentially inhibits the growth of EBV-positive NPC cells. JQ1 induces apoptosis, decreases cell proliferation and enhances the radiosensitivity in NPC cells, especially EBV-positive cells. Significantly, JQ1-induced cell death is c-Myc-dependent. Notably, RNA-seq analysis demonstrated that JQ1 represses TP63, TP53 and their targets. JQ1 also lessens the expression of PD-L1 in NPC. Moreover, the high potency of JQ1 in NPC cells was further confirmed in vivo in CNE2-EBV+ tumor-bearing mice. These findings indicate that JQ1 is a promising therapeutic candidate for advanced NPC.

Population-based estimates are lacking for the temporal trends in the contralateral breast cancer (CBC) risk for patients with breast cancer (BC). Data for BC patients diagnosed with CBC were collected from the Surveillance, Epidemiology, and End Results database. CBC incidence was calculated using the Kaplan-Meier method and the temporal trend in CBC incidence was assessed using joinpoint regression. Survival analysis was calculated using propensity scoring (PS) and multivariate Cox regression with a competing risk model. We found that 10,944 of 212,630 patients with early-stage BC were subsequently diagnosed with secondary BC in the contralateral breast. The 5-, 10-, 15-, and 20-year cumulative CBC incidences were 1.9, 4.6, 7.6, and 10.5%, respectively. Being younger (&lt, 40 years), black, hormone receptor-negative, and having undergone radiotherapy were correlated with a high risk of CBC occurrence. CBC incidence increased continuously in the first 11 years after the initial cancer diagnosis, and the upward trend slowed from years 11 to 21, and tended to decline from years 21 to 24. CBC diagnosis was significantly and negatively associated with survival. We reported population-based estimates of the CBC occurrence pattern and risk factors. Patients are at high risk of developing CBC in the first 21 years after the initial BC diagnosis.

Zhenchong Xiong,1–3,* Guangzheng Deng,1–3,* Xinjian Huang,1–3,* Xing Li,1–3 Xinhua Xie,1–3 Jin Wang,1–3 Zeyu Shuang,1–3 Xi Wang1–3 1Department of Breast Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; 2State Key Laboratory of Oncology in Southern China, Guangzhou, China; 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, China *These authors contributed equally to this work Purpose: Bone is one of the most common sites of breast cancer metastasis, and population-based studies of patients with bone metastasis in initial metastatic breast cancer (MBC) are lacking. Materials and methods: From 2010 to 2013, 245,707 breast cancer patients and 8901 patients diagnosed with initial bone metastasis were identified by Surveillance, Epidemiology, and End Results database of the National Cancer Institute. Multivariate logistic and Cox regression were used to identify predictive factors for the presence of bone metastasis and prognosis factors. Kaplan–Meier method and log-rank test were used for survival analysis. Results: Eight thousand nine hundred one patients with initial MBC had bone involvement, accounting for 3.6% of the entire cohort and 62.5% of the patients with initial MBC. Also, 70.5% of patients with bone metastasis were hormone receptor (HR) positive (HR+/human epidermal growth factor receptor 2 [HER2]−: 57.6%; HR+/HER2+: 12.9%). Patients with initial bone metastasis had a better 5-year survival rate compared to those with initial brain, liver, or lung metastasis. HR+/HER2− and HR+/HER2+ breast cancer had a propensity of bone metastasis in the entire cohort and were correlated with better prognosis in patients with initial bone metastasis. Local surgery had significantly improved overall survival in initial MBC patients with bone metastasis. Conclusion: Our study has provided population-based estimates of epidemiologic characteristics and prognosis in patients with bone metastasis at the time of breast cancer diagnosis. These findings would lend support to optimal surveillance and treatment of bone metastasis in breast cancer. Keywords: initial metastatic breast cancer, bone, molecular subtype, survival

The microRNA, miR-200c, is involved in the tumorigenesis and progression of a variety of cancers. The purpose of this study was to investigate the expression, mechanism and prognostic roles of miR-200c in breast cancer. We found that miR-200c was downregulated in both breast cancer tissue and cell lines using quantitative real-time PCR (qRT-PCR). In situ hybridization (ISH) and microarrays showed that low miR-200c expression was associated with poor patient overall survival (OS) and disease free survival (DFS). We used luciferase reporter plasmids to find that miR-200c inhibited the AKT and ERK pathways by directly targeting KRAS. Repression of KRAS by miR-200c suppressed the proliferation and survival of breast cancer cells in vitro and in vivo. miR-200c also had an anti-tumor effect by negatively regulating KRAS in a xenograft mouse model. Our findings provide clues regarding the role of miR-200c as a tumor suppressor in breast cancer through the inhibition of KRAS translation both in vitro and in vivo. miR-200c could be a potential therapeutic target in breast cancer.

The cancer stem cell (CSC) hypothesis suggests that a subset of cancer cells possesses stem cell properties and is crucial in tumor initiation, metastasis, and drug resistance. To determine the mechanism of CSCs in breast cancer, we focused on LGR5, a marker of adult stem cells that potentially serves as a functional factor in CSCs. LGR5 overexpression was detected in breast cancer and significantly associated with breast cancer recurrence and poor outcome. LGR5 promoted cell mobility, tumor formation, and epithelial-mesenchymal transition in breast cancer cells by activating Wnt/β-catenin signaling. In addition, LGR5 was more highly expressed in tumorspheres and increased the stemness of breast cancer cells. Compared with LGR5 low-expression (LGR5low) cells, LGR5high cells exhibited CSC/tumor-initiating cell-like properties, including the formation of self-renewing spheres and high tumorigenicity. Importantly, our studies indicate that LGR5 activation of Wnt/β-catenin signaling is a possible mechanism to regulate breast CSC/tumor-initiating cell renewal. These findings indicate that LGR5 not only participates in carcinogenesis but also maintained stemness by activating Wnt/β-catenin signaling in breast cancer. Stem Cells 2015;33:2913–2924

Introduction: Specific microRNA (miRNA) expression signatures have been identified in a variety of human cancers. More recently, increasing evidence shows that miRNAs exist in human blood serum and plasma. Materials and Methods: Levels of miR-185 in plasma were measured by quantitative reverse-transcriptase polymerase chain reaction in 66 glioma patients, 11 pituitary adenoma patients, 32 meningioma patients, and 14 acoustic neuroma patients. Results: The plasma levels of miR-185 were significantly altered in glioma patients compared to normal controls. However, its levels were not observably changed in patients with other brain tumors such as meningioma, acoustic neuroma, or pituitary adenoma. Furthermore, the plasma levels of miR-185 in glioblastoma multiforme patients with operation and chemo-radiation almost revived to normal levels. Finally, we also demonstrated that low plasma miR-185 levels are correlated with poor survival in glioma patients. Conclusion: These findings suggest that plasma miR-185 has become potential biomarkers for glioma and may be useful in clinical management for glioma patients.

It has been reported that miR-22 plays an important role and may be a promising therapeutic target in cancer. In this study, we found that GLUT1 is a direct target of miR-22. The ectopic expression of miR-22 inhibited breast cancer cell proliferation and invasion by targeting GLUT1. A reverse correlation between the expression of miR-22 and GLUT1 was observed in breast cancer tissue samples. Furthermore, miR-22 was significantly correlated with the TNM stage, local relapse, distant metastasis, and survival of breast cancer patients. Our data suggest that miR-22 functions as a tumor suppressor and is a promising prognostic biomarker in breast cancer.