Gasdermin D as a potential prognosis and treatment response prediction biomarker for invasive breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12548-e12548
Author(s):  
Xianghou Xia ◽  
Wenjuan Yin ◽  
Jiefei Mao ◽  
Jiejie Hu ◽  
Dehong Zou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Invasive Breast Cancer ◽  
Response Prediction ◽  
Chemotherapy Response ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter ◽  
Treatment Response Prediction

e12548 Background: Pyroptosis is a type of inflammatory cell death mediated by gasdermins. Pyroptosis is critical for macrophage against pathogen infection. Recently growing evidences show that pyroptosis may affect development and progression of many cancers. We aim to explore the expression and related function of pyroptosis executioner Gasdermin D (GSDMD) in breast cancer. Methods: We investigated the expression level of GSDMD using TNM plotter and Breast Cancer landscape proteome with TCGA, GTEx and TARGET databases, and the prognostic value of GSDMD in invasive breast cancer using Kaplan-Meier plotter with TCGA, GEO and EGA databases. The treatment response prediction values of GSDMD in invasive breast were calculated using ROC-plotter with GEO database. Further validation of the prognostic value and chemotherapy response prediction value of GSDMD were carried out with immunohistochemical staining on tissues from 165 cases of breast cancer patients receiving neoadjuvant chemotherapy in our cancer center. Results: TNM plotter and breast cancer landscape proteome portal analysis shows that overall expression level of GSDMD in invasive breast cancer tissue is 1.67 folds higher than it is in breast normal tissues ( p=1.05*e-06). Expression of GSDMD in LuminalB subtype (p=0.019) and Her2 subtype(p=0.04) is significantly higher than it is in TNBC subtype. Calculations with Kaplan-Meier plotter show expression of GSDMD is negatively correlated with overall survival(OS), HR=0.61(0.4−0.95) p=0.027 and relapse free survival (RFS), HR =0.65(0.58−0.63), p=8.7*e-14 and distant metastasis free survival (DMFS) HR =0.75(0.61−0.91), p=0.0038 in breast cancer patients. ROC-plotter calculations show high GSDMD expression is a powerful endocrine therapy (AUC=0.731 p=6*e-09 ) and chemotherapy response (AUC=0.64 p=8*e-05 ) predictor based on 5-year RFS in overall breast cancer patients. Our IHC staining analysis shows consistent prognostic and chemotherapy prediction value of GSDMD expression in TNBC patients. Conclusions: In conclusion, our findings suggest that high expression of GSDMD is positively correlated with prognosis and therapeutic response in breast cancer. GSDMD is a promising prognostic marker and therapeutic response predictor in invasive breast cancer.

scholarly journals Expression and Prognostic Characteristics of m6 A RNA Methylation Regulators in Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Bo Zhang ◽  
Yanlin Gu ◽  
Guoqin Jiang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
High Expression ◽  
Cancer Gene ◽  
Breast Cancer Patients ◽  
Rna Methylation ◽  
Kaplan Meier ◽  
Her 2 ◽  
Kaplan Meier Plotter

PurposeN6-methyladenosine (m6A) is the most prevalent modification in mRNA methylation which has a wide effect on biological functions. This study aims to figure out the efficacy of m6A RNA methylation regulator-based biomarkers with prognostic significance in breast cancer.Patients and MethodsThe 23 RNA methylation regulators were firstly analyzed through ONCOMINE, then relative RNA-seq transcriptome and clinical data of 1,096 breast cancer samples and 112 normal tissue samples were acquired from The Cancer Gene Atlas (TCGA) database. The expressive distinction was also showed by the Gene Expression Omnibus (GEO) database. The gene expression data of m6A RNA regulators in human tissues were acquired from the Genotype-Tissue Expression (GTEx) database. The R v3.5.1 and other online tools such as STRING, bc-GeneExminer v4.5, Kaplan-Meier Plotter were applied for bioinformatics analysis.ResultsResults from ONCOMINE, TCGA, and GEO databases showed distinctive expression and clinical correlations of m6A RNA methylation regulators in breast cancer patients. The high expression of YTHDF3, ZC3H13, LRPPRC, and METTL16 indicated poor survival rate in patients with breast cancer, while high expression of RBM15B pointed to a better survival rate. Both univariate and multivariate Cox regression analyses revealed that age and risk scores were related to overall survival (OS). Univariate analysis also delineated that stage, tumor (T) status, lymph node (N) status, and metastasis (M) status were associated with OS. From another perspective, Kaplan-Meier Plotter platform showed that the relatively high expression of YTHDF3 and LRPPRC and the relatively low expression of RBM15B, ZC3H13, and METTL16 in breast cancer patients had worse Relapse-Free Survival (RFS). Breast Cancer Gene-Expression Miner v4.5 showed that LRPPRC level was negatively associated with ER and PR expression, while METTL16, RBM15B, ZC3H13 level was positively linked with ER and PR expression. In HER-2 (+) breast cancer patients, the expression of LRPPRC, METTL16, RBM15B, and ZC3H13 were all lower than the HER-2 (−) group.ConclusionThe significant difference in expression levels and prognostic value of m6A RNA methylation regulators were analyzed and validated in this study. This signature revealed the potential therapeutic value of m6A RNA methylation regulators in breast cancer.

Effect of mast cells on efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme b.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11522-11522
Author(s):  
Mark Wroblewski ◽  
Janna-Lisa Velthaus ◽  
Raimund Bauer ◽  
Volkmar Müller ◽  
Christian Schem ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Granzyme B ◽  
Resistance Mechanism ◽  
Disease Free Survival ◽  
Tissue Microarrays ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Angiogenic Therapy ◽  
Kaplan Meier

11522 Background: Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. As mast cell (MC) density is known to correlate with tumor angiogenesis, we analyzed if inhibition of MC holds potential to increase efficacy of AAT in mice and cancer patients. Methods: C57BL/6J (WT), NSG or MC-deficient KitW-sh(Wsh) mice were subcutaneously injected with Panc02, EL4 or BxPC3 cells with or without bone marrow-derived MC. Tumors were treated with 20 mg/kg of anti-VEGFR2 antibodies (DC101) or 25 mg/kg cromoglicic acid. Tissue microarrays from n = 299 breast cancer patients from the GeparQuinto Phase 3 clinical trial were stained for MC and MC numbers were correlated with clinical data. Results: We observed that absence of MC reduced tumor growth and increased the efficacy of AAT in different tumor models. Intriguingly, AAT only initially reduced microvessel proliferation but this was abrogated over time as a result of MC-mediated resistance. We show that MC secrete increased amounts of granzyme b upon therapy, which mobilizes alternative pro-angiogenic factors from the tumor matrix. These factors act beside the targeted VEGFA-VEGFR2-axis and reinduce angiogenesis despite the presence of AAT. Importantly, MC-mediated resistance could be overcome using the FDA-approved MC inhibitor cromoglicic acid. In line with our preclinical data, high intratumoral MC density correlated with disease progression in HR+ breast cancer patients when Bevacizumab was added to standard neodjuvant chemotherapy (HR 8.45, p = 0.006). Accordingly, Kaplan-Meier curves indicated that disease free survival of patients with high tumoral MC density was numerically shorter in the whole cohort and significantly shorter in the HR+ cohort upon addition of AAT to chemotherapy (p = 0.168 and p = 0.004, respectively). Conclusions: Here we unravel a novel resistance mechanism, by which MC hamper efficacy of AAT in mice and cancer patients. In preclinical models this effect could be overcome by combining AAT with an FDA-approved MC inhibitor indicating high clinical relevance. Thus, combination of FDA-approved MC inhibitors with AAT might be a suitable approach to increase efficacy of AAT in the clinic.

scholarly journals Initial Identification of UDP-Glucose Dehydrogenase as a Prognostic Marker in Breast Cancer Patients, Which Facilitates Epirubicin Resistance and Regulates Hyaluronan Synthesis in MDA-MB-231 Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 246
Author(s):  
Daiana L. Vitale ◽  
Ilaria Caon ◽  
Arianna Parnigoni ◽  
Ina Sevic ◽  
Fiorella M. Spinelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Prognostic Marker ◽  
Glucose Dehydrogenase ◽  
Breast Cancer Patients ◽  
Kaplan Meier ◽  
Initial Identification ◽  
Prognosis Marker ◽  
Kaplan Meier Plotter ◽  
Worse Prognosis

UDP-glucose-dehydrogenase (UGDH) synthesizes UDP-glucuronic acid. It is involved in epirubicin detoxification and hyaluronan synthesis. This work aimed to evaluate the effect of UGDH knockdown on epirubicin response and hyaluronan metabolism in MDA-MB-231 breast cancer cells. Additionally, the aim was to determine UGDH as a possible prognosis marker in breast cancer. We studied UGDH expression in tumors and adjacent tissue from breast cancer patients. The prognostic value of UGDH was studied using a public Kaplan–Meier plotter. MDA-MB-231 cells were knocked-down for UGDH and treated with epirubicin. Epirubicin-accumulation and apoptosis were analyzed by flow cytometry. Hyaluronan-coated matrix and metabolism were determined. Autophagic-LC3-II was studied by Western blot and confocal microscopy. Epirubicin accumulation increased and apoptosis decreased during UGDH knockdown. Hyaluronan-coated matrix increased and a positive modulation of autophagy was detected. Higher levels of UGDH were correlated with worse prognosis in triple-negative breast cancer patients that received chemotherapy. High expression of UGDH was found in tumoral tissue from HER2--patients. However, UGDH knockdown contributes to epirubicin resistance, which might be associated with increases in the expression, deposition and catabolism of hyaluronan. The results obtained allowed us to propose UGDH as a new prognostic marker in breast cancer, positively associated with development of epirubicin resistance and modulation of extracellular matrix.

scholarly journals CXCL2 as a Prognostic Marker in Breast Cancer is Associated with Immune Infiltration and Regulated by miR-215

2020 ◽  
Author(s):  
Jia-Xiang An ◽  
Ying-Ying Chen ◽  
Zhao-Sheng Ma ◽  
Wen-Jie Yu ◽  
Jin-Xi Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Time ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Clinical Prognosis ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
The Impact ◽  
Kaplan Meier Plotter ◽  
Low Expression

Abstract Background: CXCL2 is a part of chemokine superfamily, which encodes secretory proteins involved in immune regulation and inflammation. The correlation between CXCL2 and prognosis of different cancers, tumor infiltrating lymphocytes are not clear. Methods: We analyzed the expression of CXCL2 and its effect on clinical prognosis through Oncomine database, Tumor Immune Estimation Resource (TIMER) website, Kaplan-Meier plotter, PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). TIMER and GEPIA were used to analyze the correlation between CXCL2 and the gene marker of immune infiltration. StarBase was used to predict the miRNA that may regulate CXCL2. The relationship between miR-532-5p and CXCL2 was detected by qRT-PCR. Kaplan-Meier plotter was used to evaluate the impact of miR-532-5p on clinical prognosis. Results: PrognoScan, Kaplan-Meier plotter and GEPIA database analysis showed that low expression of CXCL2 was associated with poor disease-specific survival time (DSS), relapse-free survival time (RFS) and overall disease survival (OS) in breast cancer patients. In addition, low expression of CXCL2 was associated with poor OS and RFS in patients with lymph node positive breast cancer. CXCL2 expression was positively correlated with the infiltration of B cells, CD4+T and CD8+T cells, neutrophils and dendritic cells (DCs) in BRCA, mainly in Luminal breast cancer. MiR-532-5p can directly regulate CXCL2 expression. High miR-532-5p expression is significantly correlated with HER2 negative, grade 2 and 3 and poor OS in patients with HER+ER- breast cancer. Conclusion: CXCL2 is closely related to the prognosis and immune infiltration level of breast cancer patients, it can be regulated by miR-532-5p.

scholarly journals Side effects of adjuvant chemotherapy and their impact on outcome in elderly breast cancer patients: a cohort study

2020 ◽  
pp. FSO617
Author(s):  
Valentina Zanuso ◽  
Vittorio Fregoni ◽  
Lorenzo Gervaso
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Side Effects ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Kaplan Meier ◽  
Chemotherapy Side Effects ◽  
Dose Reductions

Aim: Breast cancer patients over the age of 65 are more likely to suffer chemotherapy side effects, with premature discontinuation, which negatively affects survival. Methods: We conducted a retrospective cohort study enrolling breast cancer patients; dose reductions or interruptions of chemotherapy have been collected, as well as side effects. Progression-free survival was determined by Kaplan–Meier and evaluated for its association with reduction/suspension. The study included 128 women (median age: 71). Results: Nineteen patients experienced cardiotoxicity, while dosage of chemotherapy was reduced in 23 patients (18.0%), and 14 (10.9%) had premature interruptions. Dose reduction/interruptions were associated with numerically worse progression-free survival (78.2 vs 94.8 months; p = 0.10). Conclusion: Reduction/discontinuation of chemotherapy due to side effects affected nearly 30% of our population, potentially worsening outcomes.

scholarly journals The tumor-infiltrating effector regulatory T cell:CD8+ lymphocyte ratio in invasive breast cancer

2019 ◽  
Author(s):  
Morihito Okada ◽  
Noriko Goda ◽  
Shinsuke Sasada ◽  
Hideo Shigematsu ◽  
Norio Masumoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Invasive Breast Cancer ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Compete Response ◽  
Infiltrating Lymphocytes

Abstract Background Tumor-infiltrating lymphocytes (TILs) in breast cancer comprise immunostimulating and immunosuppressive components. Although FOXP3+ TILs are prototypical immunosuppressive TILs, only effector regulatory T cells (eTreg), a subset of immunosuppressive FOXP3+ TILs, are undetectable on immunohistochemical staining. This study aimed to evaluate the immunosuppressive potential of eTregs and the role of prototypical immunostimulatory CD8+ TILs in invasive breast cancer. Methods Fresh TILs extracted from 84 invasive breast cancer patients were analyzed via flow cytometry. We evaluated eTregs (CD4+FOXP3highCD45RA−), other FOXP3+ Treg subsets (naïve and non-Tregs), and total CD8+CD4- TILs. Clinicopathological factors, including histopathological characteristics, were also assessed. Results The median eTreg proportion of the total CD4+TILs was 18.7% (interquartile range [IQR], 16.4–25.5%); CD8+TILs, 124% (IQR, 87.5–140%). The proportion of eTregs to total FOXP3+ TILs varied (median, 65.6%; range, 10.1–93.2%). In an immunosuppression assay, only eTregs displayed potent immunosuppression; however, other Treg subsets did not. Among 39 patients who received neoadjuvant chemotherapy, eTreg subsets and pathological compete response (pCR) did not differ significantly, while pCR rates were significantly higher among individuals with a high than those with a low CD8+/eTreg ratio (90.2% vs 33.3%; P<0.05). Among all patients, a high CD8+/eTreg ratio tended to be associated with better disease-free survival rather than a low CD8+/eTreg ratio (P=0.09). Conclusions The CD8+/eTreg ratio is simple, optimal indicator of cancer immunity, and a high CD8+/eTreg ratio enhances the prognosis and treatment response in invasive breast cancer patients. However, further studies are required to validate the present findings.

scholarly journals ACSL3 As a Potential Prognostic Biomarker in Patients With Breast Cancer

2021 ◽  
Author(s):  
Xiangyu Sun ◽  
Meng Li ◽  
Mozhi Wang ◽  
Mengshen Wang ◽  
Haoran Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Potential Function ◽  
Prognostic Value ◽  
Prognostic Biomarker ◽  
Human Protein ◽  
Breast Cancer Patients ◽  
Kaplan Meier ◽  
Human Protein Atlas ◽  
Kaplan Meier Plotter

Abstract Objective: To explore the expression pattern of long chain fatty acyl CoA synthetase 3 (ACSL3) in breast cancer, and evaluate the clinical significance of ACSL3 by analyzing potential function and prognostic value of ACSL3 in human breast carcinoma.Methods: The expression of ACSL3 in normal mammary tissues and breast tumor tissues was analyzed by GEPIA and Human Protein Atlas. The prognostic value of ACSL3 was evaluated by Kaplan–Meier plotter analysis. ACSL3 expression was analyzed by immunohistochemistry in 297 breast cancer patients from the First Hospital of China Medical University Furthermore, based on LinkedOmics database, analyses of GO and KEGG pathways were performed to identify the potential function of ACSL3. Tumor Immune Estimation Resource (TIMER) database was used to evaluate the association between ACSL3 and immune infiltration in breast cancer. Results: GEPIA and Human Protein Atlas indicated that ACSL3 was significantly upregulated in breast carcinomas. Kaplan-Meier plotter analysis showed that increased expression of ACSL3 mRNA was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in breast cancer patients. Results from immunochemical staining showed that ACSL3 was obviously related to clinicopathological features of breast cancer, and ACSL3 was highly abundant in TNBC tumors. Moreover, survival analysis of breast cancer patients demonstrated that higher ACSL3 protein expression is unfavorable prognostic biomarker in breast cancer patients. Results from TIMER database indicated that ACSL3 expression was significantly correlated with infiltration level of multiple immune cells. Further studies are needed to explore underlying mechanism of the pro-tumor effects of ACSL3 expression.Conclusions: ACSL3 may not only serve as a reliable predictive biomarker of breast cancer but also have impact on the occurrence and progression of breast cancer. Thus, ACSL3 may be an emerging therapeutic target for the development of molecular-targeted therapeutic strategies for breast cancer.

Systemic analysis of the expression levels and prognosis of breast cancer-related cadherins

2021 ◽  
pp. 153537022110104
Author(s):  
Mingfei Xu ◽  
Chaoyue Liu ◽  
Lulan Pu ◽  
Jinrong Lai ◽  
Jingjia Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Tissues ◽  
Breast Tissues ◽  
Kaplan Meier Plotter

Cadherins form connection between cells, facilitate communication, and serve as essential agents in the progression of multiple cancers. Over 100 cadherins have been identified and they are mainly divided into four groups: classical cadherins (CDHs), protocadherins (PCDHs), desmosomal (DSC), and cadherin-related proteins. Accumulating evidence has indicated that several members of the cadherins are involved in breast cancer development. Nevertheless, the expression profiles and corresponding prognostic outcomes of these breast cancer-related cadherins are yet to be analyzed. Here, we examined the expression levels and prognostic potential of these breast cancer-related cadherins from the specific databases viz. oncomine, gene expression profiling interactive analysis, human protein atlas, UALCAN, Kaplan–Meier Plotter, and cBioPortal. We found that the CDH2/11 levels were higher in breast cancer tissues, compared to healthy breast tissues, whereas with CDH3-5, PCDH8/10, and DSC3, the levels were lower in the former than in the latter. Additionally, for CDH1/6/13/17/23, PCDH7, and FAT4, trancript level alterations between breast cancer and healthy tissues varied across different databases. The CDH1 protein levels were elevated in breast cancer tissues versus healthy breast tissues, whereas the protein levels of CDH3/11 and PCDH8/10 were reduced in breast cancer, compared to healthy breast tissues. For CDH15 and CDH23, the expression levels paralleled tumor stage. Survival analysis, using the Kaplan–Meier Plotter database, demonstrated that elevated CDH1-3 levels correlated with diminished relapse-free survival in breast cancer patients. Alternately, enhanced CDH4-6/15/17/23, PCDH10, DSC3, and FAT4 levels estimated a rise in relapse-free survival of breast cancer patients. These data suggest CDH1-3 to be a promising target for breast cancer precision therapy and CDH4-6/15/17/23, PCDH10, DSC3, and FAT4 to be novel biomarkers for breast cancer prognosis.

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