HERC3 promotes YAP/TAZ stability and tumorigenesis independently of its ubiquitin ligase activity.

YAP/TAZ transcriptional co-activators play pivotal roles in tumorigenesis. In the Hippo pathway, diverse signals activate the MST-LATS kinase cascade that leads to YAP/TAZ phosphorylation, and subsequent ubiquitination and proteasomal degradation by SCFß-TrCP . When the MST-LATS kinase cascade is inactive, unphosphorylated or dephosphorylated YAP/TAZ translocate into the nucleus to mediate TEAD-dependent gene transcription. Hippo signaling-independent YAP/TAZ activation in human malignancies has also been observed, yet the mechanism remains largely elusive. Here, we report that the ubiquitin E3 ligase HERC3 can promote YAP/TAZ activation independently of its enzymatic activity. HERC3 directly binds to ß-TrCP, blocks its interaction with YAP/TAZ, and thus prevents YAP/TAZ ubiquitination and degradation. Expression levels of HERC3 correlate with YAP/TAZ protein levels and expression of YAP/TAZ target genes in breast tumor cells and tissues. Accordingly, knockdown of HERC3 expression ameliorates tumorigenesis of breast cancer cells. Our results establish HERC3 as a critical regulator of the YAP/TAZ stability and a potential therapeutic target for breast cancer.

STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential.

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5aca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis.

Identification of an immune-related gene pair signature in breast cancer.

Background: Although breast cancer outcome has improved significantly with the recent use of molecularly targeted agents, reliable prognostic signatures are still unavailable because of tumor heterogeneity. Immune processes play an important role in tumor progression. Therefore, the aim of this study was to construct a prognostic signature based on immune-related genes (IRGs). Methods: Clinical information and gene expression of 3,496 patients were extracted from eight public data sets. A total of 2,498 IRGs associated to 17 immune processes were downloaded from the ImmPort database. RNA sequencing (RNAseq) datasets [The Cancer Genome Atlas (TCGA) and GSE96058] were used as the training set (n=2,736) and all microarray datasets were used as validation set (n=760). IRGs related to prognosis were screened out from the training set and used to construct gene pairs. The Cox regression model was used, based on the immune-related gene pairs (IRGPs). The risk score of each patient was calculated and patients were stratified into high- and low-risk groups according to the optimal threshold of the risk score. Immune cell infiltration was evaluated between both groups. Results: Among the 129 prognostic-related immune genes, 8,256 IRGPs were constructed. After screening, 89 IRGPs, including 86 unique IRGs, were used in the prognostic prediction model. Patients in the high-risk group exhibited a significantly poorer overall survival (OS) both in the training set [hazard ratio (HR): 5.9, 95% confidence interval (CI): 4.61-7.54] and validation set (HR: 1.52, 95% CI: 1.16-1.98) compared to the low-risk group. In addition, patients in the high-risk group showed a significantly lower infiltration of CD8+ T cells than patients in the low-risk group. Conclusions: An independent IRGP signature was constructed. Through pairwise comparison of a set of genes, the OS of patients could be predicted. This method avoids the impact of the batch effect caused by different sequencing platforms and has a promising application prospect.

Aldehyde dehydrogenase 1 (ALDH1) immunostaining in axillary lymph node metastases is an independent prognostic factor in ALDH1-positive breast cancer.

OBJECTIVE: To determine whether aldehyde dehydrogenase 1 (ALDH1) immunostaining in axillary lymph node metastases in patients with breast cancer is associated with poor clinical prognosis. METHODS: This retrospective study reviewed data from the medical records of patients with immunohistochemistry-confirmed invasive ductal carcinoma (IDC) and 1-3 metastatic lymph nodes in the ipsilateral axilla between December 2012 and July 2015. The association between ALDH1 immunostaining in axillary lymph node metastases and clinical parameters and prognosis was analysed using χ2-test, Kaplan-Meier survival analysis, univariate and multivariate Cox regression analyses. RESULTS: A total of 229 patients with IDC were enrolled in the study. The median follow-up was 61 months (range, 20-89 months). Patients with ALDH1-positive axillary lymph node metastases had significantly shorter relapse-free survival and overall survival compared with those with ALDH1-negative axillary lymph node metastases. ALDH1 immunostaining in axillary lymph node metastases was a significant predictor of poor prognosis in univariate and multivariate analyses. CONCLUSION: This large study with long-term follow-up suggests that ALDH1 immunostaining in axillary lymph node metastases is an independent predictor of poor prognosis in patients with breast cancer. The clinical relevance of this finding should be confirmed in further well-designed prospective studies.

EZH2-Mediated microRNA-375 Upregulation Promotes Progression of Breast Cancer via the Inhibition of FOXO1 and the p53 Signaling Pathway.

Breast cancer (BC) is the most common gynecologic tumor worldwide where aberrant expression of microRNAs (miRNAs) is frequently involved. Here, we evaluated the function of miR-375 on BC development and the molecules implicated. Differentially expressed genes between tumor and paired normal tissues from BC patients were screened out by microarray analyses. miR-375 was abundantly expressed in BC tissues and cells, and it was correlated with the poor prognosis of patients. Downregulation of miR-375 was introduced into BC cell lines MCF-7 and HCC1954, after which the viability, colony formation, migration, and invasion were suppressed, while the apoptosis of cells was increased, and the xenograft tumors in nude mice were reduced as well. EZH2 increased methylation and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and increased transcription activity of miR-375, while miR-375 directly targeted FOXO1. Either overexpression of EZH2 or downregulation of FOXO1 blocked the functions of anti-miR-375 in cells and animals. FOXO1 was found as an activator of the p53 signaling pathway. This study showed that miR-375 is an important oncogene in BC. EZH2 is an upstream regulator of miR-375 through mediating the methylation of STAT3, while FOXO1 is a downstream target mRNA of miR-375 that activates the p53 signaling pathway to suppress BC development.

Application of neoadjuvant chemotherapy combined with anlotinib in occult breast cancer: A case report and review of literature.

BACKGROUND: Occult breast cancer (OBC) is a special type of breast cancer presenting as axillary lymph node metastasis with undetectable primary lesions in the breast. Due to its low incidence and unique clinical manifestations, there is a lack of consensus on the diagnosis and treatment of OBC. We report a case of OBC treated with neoadjuvant chemotherapy combined with anlotinib. The treatment was well tolerated, and the patient achieved a pathologic complete response. CASE SUMMARY: A 53-year-old woman presented with a lump in her right axillary area with no primary lesions in the breast. Pathological biopsy confirmed right axillary metastatic carcinoma. Immunohistochemical staining results were positive for progesterone receptor, cytokeratin 7, specific breast markers GATA3 and gross cystic disease fluid protein-15. Tumor cells were negative for estrogen receptor, human epidermal growth factor receptor-2, cytokeratin 5/6, cytokeratin 20, and villin. The patient was diagnosed with OBC, and she underwent neoadjuvant chemotherapy combined with anlotinib. Mastectomy plus axillary lymph node dissection was performed. The patient achieved pathologic complete response with no residual invasive tumor cells in the breast or axillary lymph nodes. Postoperatively, she received adjuvant radiotherapy and endocrine therapy. CONCLUSION: Neoadjuvant chemotherapy and anlotinib had good efficacy and safety in the treatment of OBC and may be a new therapeutic option.

Giant Fungated Locally Advanced Breast Carcinoma Responded to Hypofractionated Radiotherapy Combined with Apatinib: A Case Report and Literature Review.

Locally advanced breast cancer (LABC) is frequently encountered in clinical practice. Primary systemic therapy is regarded as the cornerstone of LABC management to downstage the disease and enable surgery. However, multiple lines of systemic agents may fail to control tumor growth in a considerable number of patients, and few options remain available for such patients. Here, we present a case of triple-negative, right breast cancer that progressed aggressively despite 3 lines of standard chemotherapy. The patient suffered from severe skin ulceration, bleeding, pain, infection, and fungation. The small-molecular tyrosine kinase inhibitor (TKI) apatinib was initiated, which targets vascular endothelial growth factor receptor 2 (VEGFR2). The patient then underwent hypofractionated irradiation applied to the whole right breast at 40 Gy/8 f. The tumor responded dramatically to this combination, and a near-complete remission (CR) response was achieved 2 months after irradiation. Our case is novel and instructional and demonstrated the efficacy and safety of hypofractionated irradiation combined with antiangiogenesis for the treatment of intractable LABC, shedding light on this difficult situation. In the near future, large-scale clinical trials will be initiated to further explore this issue.

Higher efficacy and reduced adverse reactions in neoadjuvant chemotherapy for breast cancer by using pegylated liposomal doxorubicin compared with pirarubicin.

The present study aimed to investigate the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in preoperative neoadjuvant chemotherapy for patients with breast cancer by comparing with conventional anthracycline. This study is a non-randomized controlled trial. Prospective analysis was conducted after matching as required. A total of 146 patients with confirmed diagnosis of breast cancer by histopathological examinations were enrolled into the observation group and control group in 1:1 ratio. Each of the cases in the observation group was required to correspond to another in the control group according to the requirements including age, molecular subtype, axillary node status, and regimen of the preoperative neoadjuvant chemotherapy. The chemotherapy was based on regimens consisting of anthracyclines, paclitaxel or docetaxel, and/or platinum. PLD was used at least twice in the observation group, with traditional anthracycline as a contrast in the control group. Clinical responses as well as cardiac side effects and other adverse reactions were evaluated by clinical and imaging examinations such as electrocardiogram (ECG) and color Doppler ultrasound during the chemotherapy. Pathologic examinations were performed following the surgeries after preoperative neoadjuvant chemotherapy. All the patients in both groups completed the preoperative neoadjuvant chemotherapy according to their original regimens. The postoperative pathological evaluation revealed a higher pathologic complete response (PCR) rate and significantly more patients of grade V of the Miller-Payne grading system in the observation group as compared to the control group (p = 0.047). In addition, the observation group recorded an evidently lower occurrence of the adverse cardiac events (p = 0.014), ECG changes (p = 0.048), and the relatively severe adverse reactions such as myelosuppression. Compared with conventional anthracycline drugs, PLD has a better pathologic response and safety performance, as well as a similar clinical effectiveness in preoperative neoadjuvant chemotherapy for breast cancer.

Hard antler extract inhibits invasion and epithelial-mesenchymal transition of triple-negative and Her-2+ breast cancer cells by attenuating nuclear factor-κB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Hard antler extract (HAE) is a traditional Chinese medicine and has potent antitumor, antioxidative, anti-inflammatory, and immunomodulatory activities. Previous studies have demonstrated that HAE can inhibit human prostate cancer metastasis and murine breast cancer proliferation. However, the effect of HAE on human breast cancer cells has not been clarified. AIM OF THE STUDY: To investigate the effects and underlying mechanism of HAE on self-renewal of stem-like cells and spontaneous and transforming growth factor (TGF)-ß1-enhanced wound healing, invasion and epithelial-mesenchymal transition (EMT) in breast cancer cells. METHODS: HAE was prepared from sika deer by sequential enzymatic digestions and the active compounds were determined by HPLC. The effects of HAE on the viability, mammosphere formation, wound healing and invasion of MDA-MB-231 and SK-BR3 cells were determined. The impact of HAE treatment on spontaneous and TGF-ß1-promoted EMT and the nuclear factor (NF)-κB signaling in breast cancer cells was examined by quantitative RT-PCR and western blotting. RESULTS: Treatment with HAE at varying concentrations did not change the viability of breast cancer cells. However, HAE at 0.25 or 0.5 mg/mL significantly reduced the number and size of formed mammospheres, and inhibited spontaneous and TGF-ß1-enhanced wound healing, invasion and EMT in MDA-MB-231 and SK-BR3 cells in a dose-dependent manner. TGF-ß1 treatment significantly decreased IκBα expression and increased NF-kBp65 phosphorylation in breast cancer cells, indicating that TGF-ß1 enhanced NF-κB signaling. In contrast, HAE treatment attenuated the spontaneous and TGF-ß1-enhanced NF-κB signaling in breast cancer cells. CONCLUSION: Our data indicated that HAE inhibited the self-renewal of stem-like cells and spontaneous and TGF-ß1-enhanced wound healing, invasion and EMT in breast cancer cells by attenuating the NF-κB signaling in vitro.

Unexpected massive bleeding caused by extensive maxillary osteonecrosis in a breast cancer patient: a case report.

Diphosphonate application is routinely recommended to treat bone metastasis (BM) in cancer patients. However, the severe side effects of diphosphonate, especially after long-term use, are often overlooked by clinicians. In this article, we describe a case in which a heavily-treated breast cancer patient, suffered from massive bleeding as a result of maxillary osteonecrosis by zoledronic acid (ZA) and apatinib. In October 2018, a 48-year-old Chinese female with breast cancer presented at our department with brain metastases. The patient had experienced progression multiple times and had received several lines of systemic interventions. ZA was administered monthly for a rather long period of 37 months. She also took 250 mg of apatinib, a small molecular tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor 2, daily for 11 days. However, massive bleeding from the oral and nasal cavity occurred that could not be alleviated by conventional means. Computed tomography revealed severe destruction and loss of the right maxillary bone and maxillary sinus wall. A pathological examination of the exfoliated bone tissue further confirmed that the patient was suffering from necrosis rather than metastasis. An emergency interventional embolization was performed, and the bleeding was stopped. In this case, maxillary osteonecrosis developed from the antiresorptive agents. Antiangiogenesis drugs should be avoided whenever possible. In clinical practice, the high risk of osteonecrosis needs to be carefully considered. Further, care needs to be taken to ensure osteonecrosis is not misdiagnosed as BM, especially in stage IV patients. Pathology is a prerequisite for the timely and correct diagnosis and management. Life-threatening toxicity such as massive bleeding, should be avoided to ensure that patients receive adequate antitumor treatments.

Comparison of clinicopathological characteristics and prognosis among patients with pure invasive ductal carcinoma, invasive ductal carcinoma coexisted with invasive micropapillary carcinoma, and invasive ductal carcinoma coexisted with ductal carcinoma in situ: A retrospective cohort study.

This paper aimed to analyze the clinicopathological characteristics of invasive ductal carcinoma with an invasive micropapillary carcinoma component (IDC + IMPC), invasive ductal carcinoma with a ductal carcinoma in situ component (IDC + DCIS), and compare the clinicopathological characteristics and prognosis to those of IDC.A total of 1713 patients (130 IDC + IMPC cases, 352 IDC + DCIS cases, and 1231 pure IDC cases) who underwent appropriate surgery from June 2011 to September 2017 were retrospectively selected.Compared to the pure IDC and IDC + DCIS patients, the IDC + IMPC patients presented with more aggressive characteristics, such as a higher proportion of vascular invasion (P < .001), fewer progesterone receptor (PR)-positive patients (P < .001), a lower proportion of cases in American Joint Committee on Cancer stage I (P < .001), a higher recurrence risk (P < .001), more deaths (P < .001), and more metastatic cases (P < .001). Compared to the pure IDC and IDC + IMPC patients, the IDC+DCIS patients presented with less aggressive characteristics, such as a higher proportion of estrogen receptor-positive patients (P < .001) and PR-positive patients (P < .001), a lower proportion of cases with nerve invasion (P < .001) and vascular invasion (P < .001), a higher proportion of cases in American Joint Committee on Cancer stage I (P < .001), fewer deaths (P < .001), and fewer metastatic cases (P < .001). The patients with IDC + DCIS had significantly better disease-free survival (DFS) and overall survival (OS) compared to those with pure IDC and IDC + IMPC (P < .001). The patients with IDC + IMPC had significantly worse DFS and OS compared to those with pure IDC and IDC + DCIS (P < .001). In univariate analysis, the presence of an IMPC component in IDC (P = .007), estrogen receptor status (P = .05), and PR status (P = .003) were factors associated with OS. In multivariate analysis, coexisting IMPC (P = .04) was the only independent prognostic factor associated with OS.Compared to IDC and IDC + DCIS, IDC + IMPC had more aggressive characteristics and significantly worse DFS and OS. Compared to IDC and IDC + IMPC, IDC + DCIS had less aggressive characteristics and significantly better DFS and OS.

The SCIFF-Derived Ranthipeptides Participate in Quorum Sensing in Solventogenic Clostridia.

Ranthipeptides, defined as radical non-α thioether-containing peptides, are a newly emerging class of natural products belonging to the ribosomally synthesized and post-translationally modified peptide (RiPP) superfamily. Ranthipeptides are shown to be widespread in the bacterial kingdom, whereas heretofore their biological functions remain completely elusive. In this work, putative ranthipeptides are investigated from two solventogenic clostridia, Clostridium beijerinckii and Clostridium ljungdahlii, which are derived from the so-called six Cys in forty-five residues (SCIFF) family of precursor peptides. A series of analysis show that these two ranthipeptides participate in quorum sensing and controlling cellular metabolism. These results highlight the diverse biological functions of the ever-increasing family of RiPP natural products and showcase the potential to engineer industrially interesting organisms by manipulating their RiPP biosynthetic pathways.

Opening label, dynamic prospective cohort study on the small focus less than 1.0 cm shown by type B ultrasound in breast.

BACKGROUND: A consensus has not been achieved regarding the treatment of small nonpalpable breast lesions, and the purpose of this study was to prospectively investigate nonpalpable lesions less than 1.0 cm in diameter to explore the risk factors for such lesions and determine appropriate treatment of such kind of lesions. METHODS: A total of 1039 patients with small lesions less than 1.0 cm in diameter who underwent mammography and ultrasound from 2009 to 2010 in our institution were prospectively enrolled. Among them, 80 patients underwent biopsy, whose lesions grew by more than 30% of its original size, with an unclear boundary or irregular shape. All patients were followed-up for an average of 24 months, and lesions identified as high-risk types, such as cancer or atypical hyperplasia, of tumors on pathological examination were labeled "meaningful lesions." Then relevant factors affecting the detection of meaningful lesions were analyzed. RESULTS: In total, 40 meaningful lesions including 2 breast cancers were detected, accounting for 3.8% and 0.2% of all patients, respectively. Univariate analysis identified smoking (P = .030), irregular shape (P = .018), unclear boundary (P = .024), and vascularization (P = .023) as risk factors for the detection of meaningful lesions (P < .05). On multivariate analysis, smoking and irregular shape were further identified as independent risk factors for the detection of meaningful lesions. CONCLUSION: The overall incidence of cancer among nonpalpable lesions with a diameter less than 1.0 cm is low. Biopsies are strongly recommended for patients who are smokers or who have small lesions with an irregular shape, whereas regular follow-up observation is likely safe for other patients with small, non-palpable breast lesions.

Prevalence of BRCA1 and BRCA2 gene mutations in Chinese patients with high-risk breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women worldwide. Here, we report the prevalence of BRCA1/2 mutations in patients with high-risk breast cancer from Inner Mongolia and Jilin, China, which was a part of a nationwide project on the detection of BRCA1/2 mutations in Chinese patients with hereditary breast cancer. METHODS: According to the criteria, index patients from a total of 245 independent families were initially recruited. All 49 exons of BRCA1 and BRCA2 and adjacent noncoding regions were screened for mutations based on next-generation sequencing from collected saliva. RESULTS: We detected 17 BRCA1/2 variants in 18 of 216 (8.3%) index patients with high-risk breast cancer. Among these, seven mutations were novel, including four BRCA1 mutations (c.123_124delCAinsAT, c.5093_5096delCTAA, c.5396-2A>G, and c.2054delinsGAAGAGTAACAAGTAAGAAGAGTAACAAGAAG), and three BRCA2 mutations (c.304A>T, c.7552_7553insT, and c.9548_9549insA). The BRCA1/2 variants were identified in 14% (8/57) of the patients with triple-negative breast cancer and in 6.3% (10/159) of the patients with non-triple-negative breast cancer. There was no significant difference between the two groups (p = 0.07). A higher frequency for BRCA1 mutations was observed in patients with triple-negative breast cancer than in those with non-triple-negative breast cancer (12.3% vs. 2.5%, p = 0.004). The frequencies of the BRCA2 mutations were not significantly different between patients with triple-negative breast cancer and those with non-triple-negative breast cancer (1.8% vs. 3.8%, p = 0.46). CONCLUSION: We found that patients with triple-negative breast cancer had a higher frequency of BRCA1 mutations than those with non-triple-negative breast cancer. In this study, no significant associations between the BRCA1/2 mutation status and age, family history of breast cancer, ovarian cancer, pancreatic cancer and prostate cancer, number of primary lesions, tumor size, or lymph node metastasis were observed.

Signaling pathway inhibitors target breast cancer stem cells in triple-negative breast cancer.

The present study aimed to investigate the efficacy of five signaling pathway inhibitors, N-[N-(3,5­difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, vismodegib, salinomycin, ruxolitinib and stattic, as novel therapeutic agents that target breast cancer stem cells (BCSCs) in triple-negative breast cancer (TNBC). The in vitro anti-proliferative, anti-invasive, pro-apoptotic and inhibitory effects on BCSC self-renewal of these signaling pathway inhibitors on the TNBC stem cell line HCC38 were examined by MTT assays, Matrigel invasion assays, flow cytometry and suspension mammosphere assays, respectively. For the in vivo study, another TNBC stem cell line, HCC1806, pretreated with these signaling pathway inhibitors, was inoculated into female nonobese diabetic/severe combined immunodeficient mice, and the tumor volumes were measured following tumor formation. Treatment of HCC38 cells with each signaling pathway inhibitor significantly decreased TNBC cell proliferation, cell invasion and mammosphere formation while inducing cell apoptosis by inhibiting the protein expression or phosphorylation of downstream signaling molecules. In the xenograft mouse models, tumor formation and growth of HCC1806 cells pretreated with each signaling pathway inhibitor were effectively suppressed. Treatment with these signaling pathway inhibitors may provide a novel therapeutic strategy against TNBC by targeting BCSCs, thus providing promising insight for clinical applications in patients with TNBC.

A near-infrared xanthene fluorescence probe for monitoring peroxynitrite in living cells and mouse inflammation model.

Peroxynitrite (ONOO-) plays important roles in the regulation of many physiological and pathological processes, and an increase in its levels is related to numerous diseases. Thus, accurate detection of ONOO- in physiological conditions is imperative for elucidating its functions. However, studies on high signal-to-noise-ratio (SNR) fluorescence imaging of ONOO-in vivo for its detection are currently lacking. Thus, a novel NIR xanthene fluorescence probe (NOF2) for the endogenous detection of ONOO- is designed and synthesized. The fluorescence of the NOF2 probe is pre-quenched by the hydroxyl protection group of diphenyl phosphinate. Additionally, the NOF2 probe exhibits good selectivity and sensitivity for ONOO- with a low detection limit of 0.40 µM. Importantly, the NOF2 probe displays good performances for the detection of endogenous ONOO- not only in living cells but also in a mouse inflammation model. This demonstrates its great potential for applications involving the detection of ONOO- both in vitro and in vivo to explore the roles of ONOO- in different physiological systems.

Nogo-B receptor increases the resistance to tamoxifen in estrogen receptor-positive breast cancer cells.

BACKGROUNDS: Tamoxifen is typically used to treat patients with estrogen receptor alpha (ERα)-positive breast cancer. However, 30% of these patients gain acquired resistance to tamoxifen during or after tamoxifen treatment. As a Ras modulator, Nogo-B receptor (NgBR) is required for tumorigenesis through the signaling crosstalk with epidermal growth factor (EGF) receptor (EGFR)-mediated pathways. NgBR is highly expressed in many types of cancer cells and regulates the sensitivity of hepatocellular carcinoma to chemotherapy. In this study, we found the expression of NgBR is increased in tamoxifen-resistant ERα-positive breast cancer cells. METHODS: Tamoxifen-resistant ERα-positive MCF-7 and T47D breast cancer cell lines were established by culturing with gradually increased concentration of 4-hydroxytamoxifen (4-OHT). The effects of NgBR on tamoxifen resistance was determined by depleting NgBR in these cell lines using previously validated small interfering RNA (siRNA). The effects of 4-OHT on cell viability and apoptosis were determined using well-accepted methods such as clonogenic survival assay and Annexin V/propidium iodide staining. The alteration of EGF-stimulated signaling and gene expression was determined by western blot analysis and real-time PCR, respectively. RESULTS: NgBR knockdown with siRNA attenuates EGF-induced phosphorylation of ERα and restores the sensitivity to tamoxifen in ERα-positive breast cancer cells. Mechanistically, our data demonstrated that NgBR knockdown increases the protein levels of p53 and decreases survivin, which is an apoptosis inhibitor. CONCLUSIONS: These results suggested that NgBR is a potential therapeutic target for increasing the sensitivity of ERα-positive breast cancer to tamoxifen.

Adherence to endocrine therapy among Chinese patients with breast cancer: current status and recommendations for improvement.

BACKGROUND: Postoperative endocrine therapy is known to reduce recurrence and mortality in patients with estrogen receptor (ER)- or progestogen receptor (PR)-positive breast cancer. Correlates and determinants of compliance with endocrine therapy among Chinese patients with breast cancer are not known. The aim of this study was to elucidate the efficacy and adherence of endocrine therapy in China and suggest effective improvements on the adherence. PATIENTS AND METHODS: We analyzed the survival of 1,110 patients eligible for endocrine therapy and adherence of 699 patients to endocrine therapy. Kaplan-Meier curves, log-rank tests and Cox proportional hazard models were used to evaluate survival, and logistic regression models were used to assess variables associated with treatment adherence. RESULTS: Long-term endocrine therapy was associated with lower recurrence rate (HR 0.72; 95% CI 0.56-0.93; p=0.013). Adherence to endocrine therapy was only 63.1%. Sociodemographic characteristics of patients, clinical- and medication-related characteristics and patients' attitudes were associated with adherence to endocrine therapy. CONCLUSION: Adherence to endocrine therapy in Chinese patients with ER+/PR+ breast cancer was <65%. Both patients and physicians should take progressive steps to improve the rate of adherence.