Recently, the inflammatory cytokine IL-6 has been reported as a potent inducer of epithelial-mesenchymal transition (EMT) in breast cancer cells with an epithelial phenotype. Furthermore, EMT induces stem cell features in normal and transformed mammary cells. We explored whether IL-6-induced EMT promoted the generation of breast cancer stem-like cells (BrCSCs) in epithelial-like breast cancer cells, and whether the cytokines EGF and bFGF, analogous to IL-6, per se induced epithelial-mesenchymal transition, resulting in the enrichment of BrCSCs in mammosphere cultures. Herein, we provide evidence that IL-6 is capable of generating CD44+ cells with stem-like properties through induction of the EMT in the epithelial-like T47D breast cancer cells. We also show that mammosphere cultures of epithelial-like breast cancer cells, T47D, MCF7, ZR-75-1 and MDA-MB-453 cells, consistently generated stem-like cancer cells solely as a result of the EGF and bFGF cytokines in the mammosphere media mediating EMT. This finding demonstrated the link between the inflammatory cytokine IL-6 and BrCSCs and identified an important mechanism for the enrichment of BrCSCs in mammosphere cultures. Thus, EMT appears to be a critical mechanism for the induction of cancer cells with stem-like properties, and EMT of non-stem cancer cells could be a source of CSCs.
The deubiquitinase enzyme RPN11 is involved in oncogenesis in various types of cancer. However, in breast cancer, the expression levels, prognostic relevance and biological function of RPN11 remains unclear. In the present study, RPN11 expression levels in breast cancer tissues and adjacent non‑tumor tissues were determined by reverse transcription‑quantitative polymerase chain reaction and immunohistochemical staining, and the association of RPN11 with clinicopathological features of breast cancer was evaluated. RPN11 expression was upregulated in breast cancer tissues compared with healthy tissues. Additionally, high expression levels of RPN11 may be an indicator of poor prognosis, as validated by a breast cancer cohort from the Gene Expression Omnibus database. Knockdown of RPN11 in MDA‑MB‑231 and T47D cells significantly reduced cell proliferation and enhanced G0/G1 arrest and apoptosis. Exogenous overexpression of RPN11 in MCF7 and Hs578T cells promoted cell growth and inhibited apoptosis. In addition, knockdown of RPN11 abrogated cell migration and reduced epithelial‑mesenchymal transition. In conclusion, these findings suggested that RPN11 may function as an oncogene and its upregulation in breast cancer suggests that it may be a therapeutic target.
Background: One year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab. Methods: A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled. Results: Six studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03-1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01-1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09-1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43-0.62; p < 0.00001). Conclusions: Though correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.
BackgroundYoung breast cancer occupies a higher and higher proportion of breast cancer, especially in Asia, and is associated with a more unfavorable prognosis compared with the disease arising in older women. However, the poor prognosis of young breast cancer cannot be fully explained by the clinical and molecular factors.MethodsThis study investigated 1125 Chinese breast cancer patients diagnosed from 2009 to 2013. A data mining of gene expression profiles was performed for the young and older breast cancer patients, identifying significantly differentially expressed genes. Quantitative RT-PCR, Western blotting and immunohistochemistry assay were carried out for the clinical sample validations.ResultsThe investigation firstly displayed that young patients (≤45 years) accounted for 47.6 % (535/1125) of breast cancer, and clinically associated with some unfavorable factors related to poor prognosis, such as invasive pathological type, high tumor grade, lymph node positive, ER negative and triple-negative subtype. Subsequently, 553 significantly differentially expressed genes were identified by the data mining. Of them, a set of genes related to immune function were observed to be up-regulated in young patients with breast cancer. Impressively, the CXCL13 (C-X-C motif chemokine 13) expression level showed the most significant difference (FC = 2.64, P = 8.2 × 10−4). Furthermore, the validations with clinical samples and correlation analysis demonstrated that CXCL13 was indeed highly expressed in young breast cancer and closely associated with some prognostic factors including lymph node positive and ER negative.ConclusionThis is the first to indicate the clinical relevance of CXCL13 to young breast cancer and represents a potential therapeutic target for young breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0521-1) contains supplementary material, which is available to authorized users.
Abstract. Breast cancer is the most frequently diagnosed malignancy in women. However, the molecular mechanisms underlying breast cancer pathogenesis are not fully understood. The present study examined the role of miR-433 in breast cancer and investigated its underlying molecular mechanisms of action. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to analyze the level of microRNA (miRNA/miR)/mRNA and protein expression, respectively. Additionally, MTT assay was used to determined cell proliferation and viability. Cell apoptosis was measured by flow cytometry. A dual-luciferase reporter assay was used to confirm the identity of the downstream target of miR-433. The results revealed that miR-433 was downregulated in breast cancer tissues and cell lines. Overexpression of miR-433 inhibited cell proliferation and cell viability in BT-549 cells, whereas downregulation of miR-433 increased cell proliferation and cell viability in MDA-MB-231 cells. Further flow cytometry analysis revealed that miR-433 was able to induce apoptosis and also alter the levels of proteins expression of B-cell lymphoma-2 and Bcl-associated X. Bioinformatics analysis showed that RAC-γ serine/threonine-protein kinase (AKT3) was one of the downstream targets of miR-433, and luciferase reporter assay further confirmed that AKT3 is a direct target of miR-433. The knockdown of AKT3 was able to inhibit proliferation and viability in BT-549 cells. Overexpression of AKT3 prevented the inhibitory effects of miR-433 on proliferation and viability in BT-549 cells. The level of AKT3 mRNA expression was upregulated in breast cancer tissues compared with normal tissues and was inversely correlated with miR-433 expression levels. In summary, the results of the present study results indicate that the tumor-suppressive role of miR-433 may be mediated by regulating AKT3. miR-433 may therefore serve as a potential therapeutic target for breast cancer.
BackgroundIt is controversial for prognosis of invasive micropapillary carcinoma (IMPC) compared with invasive ductal carcinoma (IDC) of the breast. To better understand the difference between IMPC and IDC prognoses, we conducted this retrospective study.MethodsData from 33 patients with IMPC were retrospectively reviewed, and the clinicopathologic characteristics and survival status were compared with those of 347 patients with IDC who were treated during the same period.ResultsThe IMPC cases were of larger tumor size, greater proportion of nodal involvement, and an increased incidence of lymphovascular invasion compared with IDC cases. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and failure-free survival (FFS) rates were not significantly different between IMPC and IDC. The 3-year OS rate was 97 vs 94.2 % for the IMPC and IDC patients, respectively. The 3-year FFS rate was 87.9 vs 86.2 % for the IMPC and IDC patients, respectively. For IMPC patients, the 3-year LRFS rate was 93.9 % and in IDC patients was 89.0 %. The 3-year DMFS rates of IMPC patients was 90.9 % and IDC patients was 89 %.ConclusionsIMPC had poor clinical characteristics, but it showed no difference in OS, FFS, LRFS, and DMFS compare with IDC.
ABTSRACT: Biodegradable plastics based on soy dreg (SD) were prepared with glycerol as a plasticizer via compression molding at 110–160°C. The effects of the glycerol content and molding temperature on the processability and mechanical properties were investigated. For enhanced water resistivity of the SD plastics, thermoplastic benzyl konjac glucomannan (B‐KGM) films were covered on SD sheets in a lamination compression process, and SD/B‐KGM (SB) composite sheets were obtained. The structure and properties of the SB sheets were studied with Fourier transform infrared spectroscopy, dynamic mechanical thermal analysis (DMTA), scanning electron microscopy, and tensile testing. The results indicated that the tensile strength of the SB sheets was enhanced to 13.2 MPa in the dry state and to 11.4 MPa in the wet state. The water resistivity of the SB sheets with B‐KGM covers increased from 0.03 to 0.86 with an increase in the B‐KGM thickness from 0 to 35 μm. The multipeaks of a tan δ relaxation that appeared in the DMTA spectra for SB series sheets were due to multicomponents such as soy protein, cellulose, polysaccharide, and B‐KGM. The tan δ transition temperature and the decomposition temperature of cellulose in SB sheets were higher than those in SD sheets without B‐KGM covers. This work provided a simple way of improving the compression‐molding processability and water resistivity of SD plastics for practical applications. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3790–3796, 2003
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