scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Immunohistochemical analysis of CD155 expression in triple-negative breast cancer patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253176
Author(s):  
Katsuhiro Yoshikawa ◽  
Mitsuaki Ishida ◽  
Hirotsugu Yanai ◽  
Koji Tsuta ◽  
Mitsugu Sekimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Histological Grade ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Antitumor Immunotherapy

Introduction CD155 is an immune checkpoint protein. Its overexpression is an indicator of poor prognosis in some types of cancer. However, the significance of CD155 expression in patients with triple-negative breast cancer, and the relationship between CD155 and programmed death-ligand 1 (PD-L1) expression, have not yet been analyzed in detail. Methods Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of CD155 and PD-L1 in 61 patients with triple-negative breast cancer. Relapse-free survival and overall survival rates were compared according to CD155 expression. The correlation between CD155 expression and clinicopathological factors, including PD-L1 expression (using SP142 and 73–10 assays), was also examined. Results CD155 expression was noted in 25 patients (41.0%) in this cohort. CD155 expression did not correlate with pathological stage, histological grade, Ki-67 labeling index, or stromal tumor-infiltrating lymphocytes. Only PD-L1 expression in tumor cells by SP142 assay significantly correlated with CD155 expression (p = 0.035); however, PD-L1 expression in tumor cells by 73–10 assay did not show a correlation (p = 0.115). Using the 73–10 assay, 59% of patients showed CD155 and/or PD-L1 expression in tumor cells. Moreover, using the SP142 assay, 63.3% of patients showed CD155 and/or PD-L1 expression in immune cells. CD155 expression did not correlate with either relapse-free survival or overall survival (p = 0.485 and 0.843, respectively). Conclusions CD155 may be a novel target for antitumor immunotherapy. The results of this study indicate that CD155 may expand the pool of candidates with triple-negative breast cancer who could benefit from antitumor immunotherapy.

Impact of chemotherapy dose-related factors on survival in breast cancer patients treated with adjuvant anthracycline-based chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 668-668 ◽  
Author(s):  
I. Chirivella ◽  
B. Bermejo ◽  
A. Insa ◽  
A. Perez-Fidalgo ◽  
A. Magro ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Negative Impact ◽  
Histological Grade ◽  
Menopausal Status ◽  
Dose Intensity ◽  
Disease Stage ◽  
Related Factors ◽  
Ct Dose ◽  
The Impact

668 Background: The relationship between chemotherapy (CT) dose intensity and patient (pt) outcome in the management of early stage breast cancer (EBC) is still controversial. Although randomised clinical trials have provided evidence that supports the delivery of full standard doses of CT on schedule, precise thresholds for CT dose-related factors and their impact on survival-related endpoints have not yet been fully defined. The objective of this project is to assess the impact of CT dose-related factors on event-free and overall survival in a large group of EBC pts treated with anthracycline-based chemotherapy. Methods: A total of 1056 EBC (stage I-II-IIIA) cases diagnosed and treated from January 1980 to December 2000 were retrospectively studied. All of them received adjuvant anthracycline non-taxanes-based CT. Consecutive charts from 793 pts that were fully completed were included in the analysis. Survival-related endpoints were analysed through Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards models. Results: With a median follow-up of 10.0 years, pts exposed to either > 2 cycle-delay (delay at any cycle defined as ≥ 3 days vs. plan), or ≥ 15 day-delay across the whole CT regimen, or < 95% relative dose intensity (RDI) showed significantly worse 10-year Event-Free Survival (EFS) and Overall Survival (OS) as compared to pts with no dose delay/reduction (data shown below). Controlling for age at diagnosis, disease stage, histological grade, menopausal status and year of treatment did not modify these results. Conclusions: Based on this preliminary analysis, CT dose delays and reductions in EBC pts treated with adjuvant anthracycline-based regimens have a significantly negative impact on EFS and OS. [Table: see text] No significant financial relationships to disclose.

scholarly journals Immunohistochemistry for Thymidine Kinase-1 (TK1): A Potential Tool for the Prognostic Stratification of Breast Cancer Patients

2021 ◽  
Vol 10 (22) ◽  
pp. 5416
Author(s):  
Giuseppe Nicolò Fanelli ◽  
Rosa Scarpitta ◽  
Paola Cinacchi ◽  
Beatrice Fuochi ◽  
Anna Szumera-Ciećkiewicz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Thymidine Kinase ◽  
Histological Grade ◽  
Her2 Status ◽  
Breast Cancer Patients ◽  
Thymidine Kinase 1 ◽  
Ki 67 ◽  
Pyrimidine Nucleotide ◽  
Prognostic Stratification ◽  
The Impact

Breast cancer (BC) is the most frequent non-cutaneous malignancy in women. Histological grade, expression of estrogen and progesterone receptors (ER and PgR), overexpression/amplification of the human epidermal growth factor receptor 2 (HER2) oncogene, and proliferative activity measured with ki-67 provide important information on the biological features of BC and guide treatment choices. However, a biomarker that allows a more accurate prognostic stratification is still lacking. Thymidine kinase-1 (TK1), a ubiquitous enzyme involved in the pyrimidine nucleotide recovery pathway, is a cell-proliferation marker with potential prognostic and predictive impacts in BC. Eighty (80) cases of invasive BC with a long-term follow-up were retrospectively selected, and clinicopathological data were collected for each patient. TK1 tissue expression was evaluated immunohistochemically. Data suggested that TK1 expression levels are positively correlated with ER and PgR expression, and negatively correlated with HER2 status and the impact on patients' distant recurrence-free survival (DRFS): in detail, among patients undergoing adjuvant chemotherapy, lower TK1 levels are correlated with better DRFS. Therefore, these results contribute to furthering the knowledge of TK1, suggesting a possible and important role of this enzyme as a biomarker in the stratification of BC patients.

scholarly journals 6-lncRNA Assessment Model for Monitoring and Prognosis of HER2-Positive Breast Cancer: Based on Transcriptome Data

2021 ◽  
Vol 27 ◽  
Author(s):  
Xiaoming Zhang ◽  
Haiyan Zhang ◽  
Jie Li ◽  
Xiaoran Ma ◽  
Zhengguo He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Assessment Model ◽  
Differentially Expressed ◽  
Rna Expression ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Background: In view of the high malignancy and poor prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, we analyzed the RNA expression profiles of HER2-positive breast cancer samples to identify the new prognostic biomarkers.Methods: The linear fitting method was used to identify the differentially expressed RNAs from the HER2-positive breast cancer RNA expression profiles in the Cancer Genome Atlas (TCGA). Then, a series of methods including univariate Cox, Kaplan-Meier, and random forests, were used to identify the core long non-coding RNAs (lncRNAs) with stable prognostic value for HER2-positive breast cancer. A clinical feature analysis was performed, and a competing endogenous RNA network was constructed to explore the role of these core lncRNAs in HER2-positive breast cancer. In addition, a functional analysis of differentially expressed messenger RNAs in HER-2 positive breast cancer also provided us with some enlightening insights.Results: The high expression of four core lncRNAs (AC010595.1, AC046168.1, AC069277.1, and AP000904.1) was associated with worse overall survival, while the low expression of LINC00528 and MIR762HG was associated with worse overall survival. The 6-lncRNA model has an especially good predictive power for overall survival (p &lt; 0.0001) and 3-year survival (the area under the curve = 0.980) in HER2-positive breast cancer patients.Conclusion: This study provides a new efficient prognostic model and biomarkers of HER2-positive breast cancer. Meanwhile, it also provides a new perspective for elucidating the molecular mechanisms underlying HER2-positive breast cancer.

scholarly journals The Value of Ultrasound Diagnosed Axillary Lymph Node in Avoiding Axillary Surgery in Early Breast Cancer Patients

2020 ◽  
Author(s):  
Na Liu ◽  
Liu Yang ◽  
Xinle Wang ◽  
Meiqi Wang ◽  
Ruoyang Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Cancer Patients ◽  
Axillary Lymph Node ◽  
Histological Grade ◽  
False Negative ◽  
Axillary Lymph ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Axillary Surgery

Abstract Background: Axillary lymph node dissection can be avoided in early stage breast cancer patients with negative sentinel lymph node biopsy. However, the possibility of avoiding axillary surgery in patients without axillary lymph node metastasis (ALNM) by preoperative imaging is still under exploration. Thus, the objectives of this study were to investigate the high-risk factors of false negative of ALNM diagnosed by preoperative ultrasound (US) and to find out who could be avoided axillary surgery in the US negative ALNM patients.Methods: This study retrospectively analyzed 3,361 patients with primary early breast cancer diagnosed in the Breast Center of the Fourth Hospital of Hebei Medical University from January 2010 to December 2012. All patients had undergone routine preoperative US and then axillary lymph node dissected. This study investigated the clinicopathological features of axillary lymph node (ALN) negative patients diagnosed by preoperative US and its correlation with prognosis. The follow-up data for disease-free survival (DFS) and overall survival (OS) were obtained from 2,357 patients. Results: The sensitivity, specificity and accuracy of axillary US in this cohort were 66.24%, 76.62% and 73.87%. The proportion of patients in the false negative group was higher than that in true negative in the group of age < 50 years old (P = 0.002), tumor size > 2cm (P = 0.008), estrogen receptor (ER) positive (P = 0.005), progesterone receptor (PR) high expression (P = 0.007), nuclear-associated antigen Ki-67 (Ki-67) >20% (P = 0.030), visible vascular tumor thrombus (P < 0.001) and histological grade>2 (P < 0.001). Prognostic analysis of false negative and true negative ultrasonographic diagnosis of ALN metastasis: when ALNM was not found by preoperative ultrasound, there was no significant difference in patients with ALNM≤3 compared with patients without lymph node metastasis in patients of age ≥ 50 years old, tumor size ≤ 2cm, Ki-67 ≤ 20%, or histological grade ≤ 2. Conclusion: The surgery of ALN may be avoided for the preoperative US diagnosed ALNs negative in early breast cancer patients who had advanced age, small tumor size, low expression of Ki-67 and low histological grade.

scholarly journals Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Ben Holmes ◽  
Seung Ho Jung ◽  
Jing Lu ◽  
Jessica A. Wagner ◽  
Liudmilla Rubbi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Current Intensity ◽  
Beneficial Effects ◽  
Group A ◽  
The Impact

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied.

Analysis of Low Estrogen Receptor (ER+) Breast Carcinomas in a Large Community Breast Cancer Center in Northern California

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S26-S27
Author(s):  
G Bulusu ◽  
K Duncan ◽  
A Wheeler
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Histological Grade ◽  
Statistical Significance ◽  
Cancer Center ◽  
Pathology Report ◽  
Breast Cancers ◽  
Breast Carcinomas ◽  
Ki 67 ◽  
Er Positive

Abstract Introduction/Objective Estrogen Receptor (ER) expression in breast cancers is a crucial factor for endocrine therapy in patients with tumors expressing ER in ≥1% of tumor cells. The 2019 guidelines published by ASCO/CAP states that breast cancers that have a 1% to 10% of cells staining Estrogen Receptor (ER) positive should be reported as ER Low Positive cases. This study aims to address this subset of low-positive ER tumors and compare the clinical features to other known breast cancer subtypes. Methods/Case Report We conducted a retrospective review of a prospectively maintained breast cancer registry from 2013 to 2021 at Mills-Peninsula Medical Center, a Sutter Health Affiliate. The study reviewed patient charts with respect to the pathology report, operative report, chemotherapy regimen, and clinical outcomes. Statistical analyses were conducted using R Project for Statistical Coding, with The Student’s T-test used to compare continuous variables. Two-sided P values less than 0.05 indicate statistical significance. Results (if a Case Study enter NA) Our study identified 1316 cases of invasive breast carcinomas, of which 29 (2.16%) demonstrated ER Low-Positive expression. We aimed to evaluate the clinical and pathological features, such as histological grade, ER, PR, HER-2, Ki-67%, and patient age for these tumors. We found that ER Low-Positive tumors demonstrated higher mean histological grade morphology (2.5 out of 3, p&lt;0.001) that was similar to that of Triple Negative Breast Cancers (TNBC) (3 of 3, p&lt;0.001) than to High ER-Positive (1.6 of 3, p&lt;0.001) cancers. Further observations, through examining proliferation rates by utilizing the Ki-67 index, indicate comparative trends between the ER Low-Positive cohort and the TNBC cohort. Conclusion The results suggest that the ER Low-Positive carcinomas, despite reported as ER-positive cases, present with similar clinicopathological features to those of ER-negative tumors. Through this study and future research, we would like to emphasize a stricter set of guidelines that can be adopted to reduce variability for reporting biomarkers. This standardization will allow oncologists to provide more appropriate treatment options and improve the quality of patient care.

NUSAP1 and KIAA0101 downregulation by neo-adjuvant therapy is associated with better outcome and survival in breast cancer.

2020 ◽  
Author(s):  
Gerardo I. Magallanes-Garza ◽  
Sandra K. Santuario-Facio ◽  
Arlina F. Varela-Varela ◽  
Servando Cardona-Huerta ◽  
Pablo Ruiz-Flores ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Expression Profiles ◽  
Pathological Response ◽  
Primary Tumors ◽  
Before And After ◽  
Neo Adjuvant Chemotherapy

Abstract Background: Studies of molecular changes occurring before and after neo-adjuvant chemotherapy (NCT) for breast cancer may unveil genetic biomarkers to predict therapy response. This study aimed at identifying genomic changes in breast primary tumors of patients under NCT. Gene expression changes were correlated with pathological response and survival.Methods: Gene expression profiles in tissue samples from pre and post NCT were obtained by a non-supervised classification analysis. Thirty-nine patients were classified according to their response to the chemotherapy as pathologic complete responders or non-responders (pCR and no-pCR, respectively). Overall survival was assessed by comparing gene expression values before NCT using the Log-rank (Mantel-Cox) test. Results: A signature constituted by 43 genes was obtained to stratify pCR and no-pCR patients after NCT (FC = + 3, FDR p -value < 0.0298). These genes were involved in regulation of the mitotic nuclear division and the anaphase-promoting complex-dependent catabolic process. Remarkably, over-expression of NUSAP1 and KIAA0101 were associated to poor overall survival. Conclusions: A new expression signature evaluating response for the neo-adjuvant chemotherapy stratified pathological response. The expression levels of NUSAP1 and KIAA0101 before and after the neo-adjuvant therapy may be useful to predict overall survival.

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