scholarly journals Inflammation promotes tumor aggression by stimulating stromal cell-dependent collagen crosslinking and stromal stiffening

2020 ◽  
Author(s):  
Ori Maller ◽  
Allison P. Drain ◽  
Alexander S. Barrett ◽  
Signe Borgquist ◽  
Brian Ruffell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cell ◽  
Lysyl Oxidase ◽  
Therapeutic Interventions ◽  
Stromal Fibroblast ◽  
Breast Cancer Patients ◽  
Collagen Crosslinks ◽  
Collagen Crosslinking ◽  
Lysyl Hydroxylase ◽  
Cancer Subtypes

AbstractCollagen deposition and stromal stiffening accompany malignancy, compromise treatment, and promote tumor aggression. Clarifying the molecular nature of and the factors that regulate extracellular matrix stiffening in tumors should identify biomarkers to stratify patients for therapy and therapeutic interventions to improve outcome. We profiled lysyl hydroxylase- and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in more aggressive human breast cancer subtypes with the stiffest stroma. These tissues also harbored the highest number of tumor-associated macrophages (TAM), whose therapeutic ablation not only reduced metastasis, but also concomitantly decreased accumulation of collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme lysyl oxidase had no impact on collagen crosslinking in PyMT mammary tumors, whereas stromal cell targeting did. Consistently, stromal cells in microdissected human tumors expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of a cohort of breast cancer patient biopsies revealed that stromal expression of lysyl hydroxylase two, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening correlated significantly disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumor aggression and identify lysyl hydroxylase two as a novel stromal biomarker.SignificanceWe show infiltrating macrophages induce stromal fibroblast, and not epithelial, expression of collagen crosslinking enzymes that drive tumor stiffening. Stromal enzyme LH2 is significantly upregulated in breast cancer patients with the stiffest stroma, the most trivalent HLCCs and the worst prognosis, underscoring its potential as a biomarker and therapeutic target.

scholarly journals DNA Methylation Based Molecular Subtypes Predict Prognosis in Breast Cancer Patients

2021 ◽  
Vol 28 ◽  
pp. 107327482098851
Author(s):  
Zeng-Hong Wu ◽  
Yun Tang ◽  
Yan Zhou
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Methylation Status ◽  
The Cancer Genome Atlas ◽  
Training Dataset ◽  
Consensus Clustering ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Novel Biomarkers

Background: Epigenetic changes are tightly linked to tumorigenesis development and malignant transformation’ However, DNA methylation occurs earlier and is constant during tumorigenesis. It plays an important role in controlling gene expression in cancer cells. Methods: In this study, we determining the prognostic value of molecular subtypes based on DNA methylation status in breast cancer samples obtained from The Cancer Genome Atlas database (TCGA). Results: Seven clusters and 204 corresponding promoter genes were identified based on consensus clustering using 166 CpG sites that significantly influenced survival outcomes. The overall survival (OS) analysis showed a significant prognostic difference among the 7 groups (p<0.05). Finally, a prognostic model was used to estimate the results of patients on the testing set based on the classification findings of a training dataset DNA methylation subgroups. Conclusions: The model was found to be important in the identification of novel biomarkers and could be of help to patients with different breast cancer subtypes when predicting prognosis, clinical diagnosis and management.

scholarly journals Clinical Significance of Annexin A2 Expression in Breast Cancer Patients

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 2
Author(s):  
Lee D. Gibbs ◽  
Kelsey Mansheim ◽  
Sayantan Maji ◽  
Rajesh Nandy ◽  
Cheryl M. Lewis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Cell Lines ◽  
Breast Cancer Subtypes ◽  
Enzyme Linked Immunosorbent Assay ◽  
Breast Cancer Patients ◽  
Serum Samples ◽  
Cancer Subtypes ◽  
Tumor Tissues

Increasing evidence suggests that AnxA2 contributes to invasion and metastasis of breast cancer. However, the clinical significance of AnxA2 expression in breast cancer has not been reported. The expression of AnxA2 in cell lines, tumor tissues, and serum samples of breast cancer patients were analyzed by immunoblotting, immunohistochemistry, and enzyme-linked immunosorbent assay, respectively. We found that AnxA2 was significantly upregulated in tumor tissues and serum samples of breast cancer patients compared with normal controls. The high expression of serum AnxA2 was significantly associated with tumor grades and poor survival of the breast cancer patients. Based on molecular subtypes, AnxA2 expression was significantly elevated in tumor tissues and serum samples of triple-negative breast cancer (TNBC) patients compared with other breast cancer subtypes. Our analyses on breast cancer cell lines demonstrated that secretion of AnxA2 is associated with its tyrosine 23 (Tyr23) phosphorylation in cells. The expression of non-phosphomimetic mutant of AnxA2 in HCC1395 cells inhibits its secretion from cells compared to wild-type AnxA2, which further suggest that Tyr23 phosphorylation is a critical step for AnxA2 secretion from TNBC cells. Our analysis of AnxA2 phosphorylation in clinical samples further confirmed that the phosphorylation of AnxA2 at Tyr23 was high in tumor tissues of TNBC patients compared to matched adjacent non-tumorigenic breast tissues. Furthermore, we observed that the diagnostic value of serum AnxA2 was significantly high in TNBC compared with other breast cancer subtypes. These findings suggest that serum AnxA2 concentration could be a potential diagnostic biomarker for TNBC patients.

scholarly journals Stromal Cell-Derived Factor 1α (SDF-1α) in Invasive Breast Cancer: Associations with Vasculo-Angiogenic Factors and Prognostic Significance

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1952
Author(s):  
Elżbieta Zarychta ◽  
Barbara Ruszkowska-Ciastek ◽  
Kornel Bielawski ◽  
Piotr Rhone
Keyword(s):  
Breast Cancer ◽  
Invasive Breast Cancer ◽  
Stromal Cell ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Roc Curve Analysis ◽  
Stromal Cell Derived Factor ◽  
A Prospective Study

(1) Background: Tumour angiogenesis is critical for the progression of neoplasms. A prospective study was designed to examine the utility of stromal cell-derived factor 1α (SDF-1α) and selected vasculo-angiogenic parameters for estimating the probability of disease relapse in 84 primary, operable invasive breast cancer (IBrC) patients (40 (48%) with stage IA and 44 (52%) with stage IIA and IIB). (2) Methods: We explored the prognostic value of the plasma levels of SDF-1α, vascular endothelial growth factor A (VEGF-A), the soluble forms of VEGF receptors type 1 and 2, and the number of circulating endothelial progenitor cells (circulating EPCs) in breast cancer patients. The median follow-up duration was 58 months, with complete follow-up for the first event. (3) Results: According to ROC curve analysis, the optimal cut-off point for SDF-1α (for discriminating between patients at high and low risk of relapse) was 42 pg/mL, providing 57% sensitivity and 75% specificity. Kaplan–Meier curves for disease-free survival (DFS) showed that concentrations of SDF-1α lower than 42 pg/dL together with a VEGFR1 lower than 29.86 pg/mL were significantly associated with shorter DFS in IBrC patients (p = 0.0381). Patients with both SDF-1α lower than 42 pg/dL and a number of circulating EPCs lower than 9.68 cells/µL had significantly shorter DFS (p = 0.0138). (4) Conclusions: Our results imply the clinical usefulness of SDF-1α, sVEGFR1 and the number of circulating EPCs as prognostic markers for breast cancer in clinical settings.

scholarly journals KBoost: a new method to infer gene regulatory networks from gene expression data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luis F. Iglesias-Martinez ◽  
Barbara De Kegel ◽  
Walter Kolch
Keyword(s):  
Breast Cancer ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Bayesian Model Averaging ◽  
Model Averaging ◽  
R Package ◽  
Breast Cancer Patients ◽  
Sources Of Information ◽  
Cancer Subtypes ◽  
Gene Regulatory

AbstractReconstructing gene regulatory networks is crucial to understand biological processes and holds potential for developing personalized treatment. Yet, it is still an open problem as state-of-the-art algorithms are often not able to process large amounts of data within reasonable time. Furthermore, many of the existing methods predict numerous false positives and have limited capabilities to integrate other sources of information, such as previously known interactions. Here we introduce KBoost, an algorithm that uses kernel PCA regression, boosting and Bayesian model averaging for fast and accurate reconstruction of gene regulatory networks. We have benchmarked KBoost against other high performing algorithms using three different datasets. The results show that our method compares favorably to other methods across datasets. We have also applied KBoost to a large cohort of close to 2000 breast cancer patients and 24,000 genes in less than 2 h on standard hardware. Our results show that molecularly defined breast cancer subtypes also feature differences in their GRNs. An implementation of KBoost in the form of an R package is available at: https://github.com/Luisiglm/KBoost and as a Bioconductor software package.

scholarly journals Serum N-glycan profiles differ for various breast cancer subtypes

2021 ◽  
Author(s):  
Gerda C. M. Vreeker ◽  
Kiki M. H. Vangangelt ◽  
Marco R. Bladergroen ◽  
Simone Nicolardi ◽  
Wilma E. Mesker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Detection ◽  
Cancer Patients ◽  
High Resolution Mass Spectrometry ◽  
Case Control ◽  
Total Serum ◽  
Screening Methods ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Control Comparison

AbstractBreast cancer is the most prevalent cancer in women. Early detection of this disease improves survival and therefore population screenings, based on mammography, are performed. However, the sensitivity of this screening modality is not optimal and new screening methods, such as blood tests, are being explored. Most of the analyses that aim for early detection focus on proteins in the bloodstream. In this study, the biomarker potential of total serum N-glycosylation analysis was explored with regard to detection of breast cancer. In an age-matched case-control setup serum protein N-glycan profiles from 145 breast cancer patients were compared to those from 171 healthy individuals. N-glycans were enzymatically released, chemically derivatized to preserve linkage-specificity of sialic acids and characterized by high resolution mass spectrometry. Logistic regression analysis was used to evaluate associations of specific N-glycan structures as well as N-glycosylation traits with breast cancer. In a case-control comparison three associations were found, namely a lower level of a two triantennary glycans and a higher level of one tetraantennary glycan in cancer patients. Of note, various other N-glycomic signatures that had previously been reported were not replicated in the current cohort. It was further evaluated whether the lack of replication of breast cancer N-glycomic signatures could be partly explained by the heterogenous character of the disease since the studies performed so far were based on cohorts that included diverging subtypes in different numbers. It was found that serum N-glycan profiles differed for the various cancer subtypes that were analyzed in this study.

scholarly journals Collagen Biosynthesis, Processing, and Maturation in Lung Ageing

2021 ◽  
Vol 8 ◽  
Author(s):  
Ceylan Onursal ◽  
Elisabeth Dick ◽  
Ilias Angelidis ◽  
Herbert B. Schiller ◽  
Claudia A. Staab-Weijnitz
Keyword(s):  
Lung Disease ◽  
Cell Function ◽  
Lysyl Oxidase ◽  
Advanced Glycation Endproducts ◽  
Mouse Lung ◽  
Chronic Obstructive ◽  
Collagen Biosynthesis ◽  
Collagen Crosslinks ◽  
Collagen Crosslinking ◽  
Chronic Lung Diseases

In addition to providing a macromolecular scaffold, the extracellular matrix (ECM) is a critical regulator of cell function by virtue of specific physical, biochemical, and mechanical properties. Collagen is the main ECM component and hence plays an essential role in the pathogenesis and progression of chronic lung disease. It is well-established that many chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) primarily manifest in the elderly, suggesting increased susceptibility of the aged lung or accumulated alterations in lung structure over time that favour disease. Here, we review the main steps of collagen biosynthesis, processing, and turnover and summarise what is currently known about alterations upon lung ageing, including changes in collagen composition, modification, and crosslinking. Recent proteomic data on mouse lung ageing indicates that, while the ER-resident machinery of collagen biosynthesis, modification and triple helix formation appears largely unchanged, there are specific changes in levels of type IV and type VI as well as the two fibril-associated collagens with interrupted triple helices (FACIT), namely type XIV and type XVI collagens. In addition, levels of the extracellular collagen crosslinking enzyme lysyl oxidase are decreased, indicating less enzymatically mediated collagen crosslinking upon ageing. The latter contrasts with the ageing-associated increase in collagen crosslinking by advanced glycation endproducts (AGEs), a result of spontaneous reactions of protein amino groups with reactive carbonyls, e.g., from monosaccharides or reactive dicarbonyls like methylglyoxal. Given the slow turnover of extracellular collagen such modifications accumulate even more in ageing tissues. In summary, the collective evidence points mainly toward age-induced alterations in collagen composition and drastic changes in the molecular nature of collagen crosslinks. Future work addressing the consequences of these changes may provide important clues for prevention of lung disease and for lung bioengineering and ultimately pave the way to novel targeted approaches in lung regenerative medicine.

scholarly journals PIWI-Like 1 and PIWI-Like 2 Expression in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2742
Author(s):  
Ramona Erber ◽  
Julia Meyer ◽  
Helge Taubert ◽  
Peter A. Fasching ◽  
Sven Wach ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Breast Cancer Subtypes ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Cancer Subtypes ◽  
Prognostic Effect ◽  
Enhanced Expression ◽  
Disease Free

PIWI-like 1 and PIWI-like 2 play a role in stem cell self-renewal, and enhanced expression has been reported for several tumor entities. However, few studies have investigated PIWI-like 1 and PIWI-like 2 expressions in breast cancer subtypes regarding prognosis. Therefore, we examined protein expression in a large consecutive cohort of breast cancer patients and correlated it to breast cancer subtypes and survival outcome. PIWI-like 1 and PIWI-like 2 expressions were evaluated using immunohistochemistry in a cohort of 894 breast cancer patients, of whom 363 were eligible for further analysis. Percentage and intensity of stained tumor cells were analyzed and an immunoreactive score (IRS) was calculated. The interaction of PIWI-like 1 and PIWI-like 2 showed a prognostic effect on survival. For the combination of high PIWI-like 1 and low PIWI-like 2 expressions, adjusted hazard ratios (HRs) were significantly higher with regard to overall survival (OS) (HR 2.92; 95% confidence interval (CI) 1.24, 6.90), disease-free survival (DFS) (HR 3.27; 95% CI 1.48, 7.20), and distant disease-free survival (DDFS) (HR 7.64; 95% CI 2.35, 24.82). Both proteins were significantly associated with molecular-like and PAM50 subgroups. Combining high PIWI-like 1 and low PIWI-like 2 expressions predicted poorer prognosis and both markers were associated with aggressive molecular subtypes.

scholarly journals USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3090
Author(s):  
Ashley Mussell ◽  
He Shen ◽  
Yanmin Chen ◽  
Michalis Mastri ◽  
Kevin H. Eng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Protein Stability ◽  
Cancer Patients ◽  
Effector Proteins ◽  
Therapeutic Interventions ◽  
Hippo Signaling ◽  
Strong Positive Correlation ◽  
Breast Cancer Patients ◽  
Loss Of Function

The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level. Using an siRNA library screen of deubiquitinating enzymes (DUBs), we identified ubiquitin specific peptidase 1 (USP1) as a novel TAZ (WWTR1) regulator. We demonstrated that USP1 interacts with TAZ and increases TAZ protein stability. Conversely, loss of function of USP1 reduces TAZ protein levels through increased poly-ubiquitination, causing a decrease in cell proliferation and migration of breast cancer cells. Moreover, we showed a strong positive correlation between USP1 and TAZ in breast cancer patients. Our findings facilitate the attainment of better understanding of the crosstalk between these pathways and may lead to potential therapeutic interventions for breast cancer patients.

scholarly journals ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis

2019 ◽  
Vol 116 (14) ◽  
pp. 6836-6841 ◽  
Author(s):  
Vinit Shanbhag ◽  
Kimberly Jasmer-McDonald ◽  
Sha Zhu ◽  
Adam L. Martin ◽  
Nikita Gudekar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lysyl Oxidase ◽  
Meta Analysis ◽  
Myeloid Cell ◽  
Breast Cancer Patients ◽  
Orthotopic Mouse Model ◽  
Copper Transporter ◽  
Cell Recruitment ◽  
Lung Carcinoma Cells ◽  
Lewis Lung Carcinoma Cells

Lysyl oxidase (LOX) and LOX-like (LOXL) proteins are copper-dependent metalloenzymes with well-documented roles in tumor metastasis and fibrotic diseases. The mechanism by which copper is delivered to these enzymes is poorly understood. In this study, we demonstrate that the copper transporter ATP7A is necessary for the activity of LOX and LOXL enzymes. Silencing of ATP7A inhibited LOX activity in the 4T1 mammary carcinoma cell line, resulting in a loss of LOX-dependent mechanisms of metastasis, including the phosphorylation of focal adhesion kinase and myeloid cell recruitment to the lungs, in an orthotopic mouse model of breast cancer. ATP7A silencing was also found to attenuate LOX activity and metastasis of Lewis lung carcinoma cells in mice. Meta-analysis of breast cancer patients found that high ATP7A expression was significantly correlated with reduced survival. Taken together, these results identify ATP7A as a therapeutic target for blocking LOX- and LOXL-dependent malignancies.

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