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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: 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

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.

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.

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.

// 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.

// 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

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

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.

Background: Breast cancer mortality has been stable or decreasing in the world, its incidence and recurrence rates have sharply risen worldwide in the recent years. Objective: To investigate the clinicopathological significance and potential function of GRP78 in the development and progression of breast cancer. To explore the effects of neoisoliquiritigenin (NISL) in breast cancer and the underlying mechanism. Method: GRP78 was detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs), and the association between GRP78 levels and clinicopathological factors and prognosis was analyzed. The functional effects of GRP78 on breast cancer were validated by an MTT assay, foci formation assay, Matrigel invasion assay and mouse xenograft assay. The effects of NISL were tested by an MTT assay, apoptosis assay and mouse xenograft assay. A LigandFit algorithm, ATPase activity assay, western blot and IHC assay were used to discover the underlying mechanism of the effects of NSIL. Results: GRP78 was highly expressed in breast cancer cell lines and tissues. In addition, high expression of GRP78 was correlated to poor outcomes and distant metastasis. Functional experiments showed that GRP78 promoted breast cancer proliferation and invasion in vitro and in vivo. NISL inhibited cell proliferation and induced cell apoptosis in breast cancer by directly binding to GRP78 to regulate the β-catenin pathway. Conclusion: Taken together, these results highlighted the significance of GRP78 in breast cancer development and suggested NISL as a natural candidate to inhibit breast cancer by targeting GRP78 and β-catenin signaling.

Background: Since inconsistent results have been reported regarding the relation between the matrix metalloproteinase-2 (MMP-2) -1306C>T polymorphism and susceptibility for breast cancer, we performed a meta-analysis to investigate the issue. Materials and Methods: An internet search of PubMed and EMBASE was performed to identify eligible studies. Pooled odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated to evaluate any association between MMP-2 -1306C>T polymorphism and breast cancer susceptibility. Results: Nine case-control studies were included in the meta-analysis, involving 9,858 cases and 10,871 controls. Overall, there was no evidence of any association between the MMP-2 -1306C>T polymorphism and breast cancer susceptibility in different genetic models (T-allele vs C-allele: OR=0.95, 95%CI, 0.82-1.10, p=0.49; TT vs CC: OR=1.03, 95%CI, 0.90-1.19, p=0.66; TT+TC vs CC: OR=0.93, 95%CI, 0.78-1.10, p=0.38; TT vs TC+CC: OR=1.02, 95%CI, 0.89-1.17, p=0.77). In the subgroup analysis by ethnicity, CC was associated with a significant increase in breast susceptibility among Latin-Americans in the dominant model (OR=0.61, 95%CI, 0.40-0.93, p=0.02), but the association disappeared in other models. No significant association was observed among Europeans, East Asians and others in different genetic models. In the subgroup analysis by their source of controls, no significant association between MMP-2 -1306C>T polymorphism and breast cancer susceptibility was noted among population-based studies and hospital-based studies in different genetic models. Conclusions: The results of this meta-analysis suggest that MMP-2 -1306C>T polymorphism is not associated with breast cancer susceptibility, although the association among Latin-Americans in the dominant model was significant.

Curcumin, a biphenyl compound derived from rhizome, is a powerful anti-cancer agent. Emodin is an active component isolated from the root and rhizome of Rheum palmatum that has been widely used in traditional Chinese medicine for the treatment of various diseases. Currently, there are no studies examining the effect of curcumin in combination with emodin on tumor cell growth. In this study, we report for the first time that combined curcumin and emodin administration synergistically inhibits proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells. Synergism is determined by the Chou-Talalay method. Moreover, we demonstrate that miR-34a is upregulated by curcumin and emodin. This microRNA helps mediate the anti-tumor effects of curcumin and emodin by downregulating Bcl-2 and Bmi-1. Our results not only provide insight into the mechanism of synergy between curcumin and emodin in breast cancer cells, but also suggest a new and potentially useful approach for breast cancer therapy.

Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer.

Objectives The purpose of this study was to investigate the potential correlation between lactate dehydrogenase A (LDHA) and AMP-activated protein kinase (AMPK) and their clinicopathologic significance in breast cancer. Materials and Methods Western blot and qRT-PCR were used to detect the expression levels of LDHA and AMPK in eight breast cancer lines and eight breast cancer tissues. In addition, LDHA and AMPK were detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs) of 112 patients. The association between LDHA and AMPK expression levels was statistically analyzed. So were the prognostic roles and clinicopathologic significances in breast cancer. Results The expression levels of LDHA and AMPK were relatively higher in triple-negative breast cancer (TNBC) cell lines than in non-triple-negative breast cancer (NTNBC) cell lines. LDHA and AMPK were also further up-regulated in TNBC tissues than in NTNBC tissues. Correlation analysis showed a positive correlation between LDHA and AMPK expression levels. Expression of LDHA and AMPK were significantly correlated with TNM stage, distant metastasis, Ki67 status and survival outcomes of patients. Patients with both positive expression of LDHA and AMPK showed shorter overall survival (OS) and disease-free survival (DFS). Conclusions These findings improve our understanding of the expression pattern of LDHA and AMPK in breast cancer and clarify the role of LDHA and AMPK as promising prognostic biomarkers for breast cancer.

Several researches reported that overexpression of SIRT1 was associated with poor survival in several human cancers. However, some researches reported that SIRT1 had an antitumor potential. The definite role of SIRT1 is not clear now, and few studies have documented the value of SIRT1 in triple-negative breast cancer (TNBC). Therefore, the aim of this study is to evaluate the role of SIRT1 in TNBC and non-TNBC for prognosis. A total of 51 TNBC patients and 83 non-TNBC patients who were diagnosed from October 2001 to September 2006 were involved in this study. Immunohistochemical staining for SIRT1 and p53 on tissue microarrays were used. Expression of SIRT1 was seen in 55 % of TNBC patients and 53 % of non-TNBC patients. Expression of SIRT1 was associated with lymph nodes status, stage, distant metastatic relapse, and p53 status in TNBC patients. Expression of SIRT1 in non-TNBC patients was significantly correlated with lymph nodes status, age, stage, distant metastatic relapse, PR status, and p53 status. SIRT1+ group was associated with shorter DFS and OS compared with SIRT1- group in TNBC, non-TNBC, and overall breast cancer patients, according to univariate Cox regression analysis. Our study provides evidence that expression of SIRT is associated with worse prognosis in TNBC and non-TNBC and SIRT1 could be a potential therapeutic target in breast cancer.

Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer (TNBC). Recent studies have demonstrated that microRNAs (miRNA) play vital roles in the development of TNBC. In this study, we found that miR-185 was strongly downregulated in TNBC tissues and cell lines and that its expression levels were associated with lymph node metastasis, clinical stage, overall survival, and relapse-free survival in TNBC. We also found that ectopic expression of miR-185 inhibited TNBC cell proliferation in vitro and in vivo. We further identified that miR-185 directly targeted DNMT1 and E2F6, which resulted in a marked increase in the expression of BRCA1 at the mRNA and protein levels in TNBC. Our data suggest that miR-185 functions as a tumor suppressor in TNBC development. It is a promising prognostic biomarker and potential therapeutic target for TNBC. Mol Cancer Ther; 13(12); 3185–97. ©2014 AACR.

Advanced breast cancer requires systemic treatment, therefore developing an efficient and safe strategy is urgently needed. To ensure the success of target therapy, we have developed a breast cancer-specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier) to target PEA-15 (phosphoprotein enriched in astrocytes) in advanced breast tumors. PEA-15 contains a death effector domain that sequesters extracellular signal-regulated kinase (ERK) in the cytoplasm, thereby inhibiting cell proliferation and inducing apoptosis. T-VISA-PEA-15 was found to be highly specific, selectively express PEA-15 in breast cancer cells, and induce cancer-cell killing in vitro and in vivo without affecting normal cells. Moreover, intravenous treatment with T-VISA-PEA-15 coupled with liposome nanoparticles attenuated tumor growth and prolonged survival in mice bearing advanced breast tumors. Importantly, there was virtually no severe toxicity when PEA-15 is expressed by our T-VISA system compared with cytomegalovirus (CMV) promoter. Thus, our findings demonstrate an effective cancer-targeted therapy that is worthy of development in clinical trials eradicating advanced breast cancer.

Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.

In Figure 1, not all of the data is included. The incorrect version of the figure represents miR-26a expression analysis in 20 breast cancer specimens and 15 normal breast tissues. The revised version includes 52 breast cancer specimens and 29 normal breast tissues. Please see the revised version of Figure 1 here

BackgroundCompared with invasive breast cancer, breast cancer in situ (BCIS) is seldom life threatening. However, an increasing incidence has been observed in recent years over the world. The purpose of our study is to investigate the epidemiological, clinical and pathological profiles of BCIS in Chinese women from 1999-2008.MethodsFour thousand and two hundred-eleven female breast cancer (BC) patients were enrolled in this hospital-based nation-wide and multi-center retrospective study. Patients were randomly selected from seven hospitals in seven representative geographical regions of China between 1999 and 2008. The epidemiological, clinical and pathological data were collected based on the designed case report form (CRF).ResultsThere were one hundred and forty-three BCIS cases in four thousand and two hundred-eleven BC patients (3.4%). The mean age at diagnosis was 48.3 years and BCIS peaked in age group 40-49 yrs (39.9%). The most common subtype was ductal carcinoma in situ (DCIS) (88.0%). 53.8% were positive for estrogen receptor (ER). Human epidermal growth factor receptor 2 (HER2) positive status was observed in 23.8% of patients. All patients underwent surgeries and 14.7% of them had breast conservation therapies (BCT) (21/143), but 41.9% accepted chemotherapy (64/143). Much less patients underwent radiotherapy (16.0%, 23/143) and among patients who had BCT, 67% accepted radiotherapy (14/21). Endocrine therapy was taken in 44.1% patients (63/143).ConclusionsThe younger age of BCIS among Chinese women than Western countries and increasing number of cases pose a great challenge. BCT and endocrine therapy are under great needs.

Background: Breast cancer patients with high proportion of cancer stem cells (BCSCs) are more chemotherapy-resistant and have unfavorable clinical outcomes. MicroRNAs (miRNAs) can function as oncogenes or tumor suppressor genes, which regulate key features of BCSCs. Since BCSCs have unique miRNA expression profile, we hypothesized that a biology-driven model based on BCSC-associated miRNAs could provide prognostic information for low recurrent-risk HR+HER2- breast cancer patients. Methods: A systematic literature reviewing suggested 50 BCSC-associated miRNAs that regulate the BCSC features. We excluded 15 of these miRNAs as they were not constantly detectable in the 40 paraffin embedded tumor samples by qRT-PCR (A pilot assay). A total of 35 BCSC-associated miRNAs were identified. We randomly assigned 303 patients into a training group (n = 202) and an internal validation (n = 101) group. We built a 10-miRNA-based classifier using a LASSO Cox model in the training group and validated its prognostic in the internal validation group, and two external independent groups of 308 patients. Results: In this multicenter study, we developed build a 10-miRNA classifier to predict disease-relapse free survival (DRFS). With this classifier, HR+HER2- breast cancer patients were classified into high-risk and low-risk group of diseases recurrence. The DFS was significantly different between these two groups in all of the patient groups. In the training group, the 5-year DRFS was 90.83% and 35.0% for the low-risk and the high-risk group, respectively (hazard ratio [HR] 15.85, 95% CI 8.15-30.82; p Interpretation: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients. This classifier may facilitate patient counseling and serve in personalized treatment for breast cancer patients. Citation Format: Chang Gong, Weige Tan, Kai Chen, Na You, Shan Zhu, Wei Luo, Xinhua Xie, Yunjie Zeng, Nengtai Ouyang, Zhihua Li, Mushen Zeng, ShiMei Zhuang, Wan-Yee Lau, Qiang Liu, Fengxi Su, Xueqin Wang, Erwei Song. Prognostic value of a BCSC-associated microRNA signature in hormone receptor-positive her2-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-139.