scholarly journals The Value of EphB2 Receptor and Cognate Ephrin Ligands in Prognostic and Predictive Assessments of Human Breast Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 8098
Author(s):  
Abdul Shukkur Ebrahim ◽  
Zeyad Hailat ◽  
Sudeshna Bandyopadhyay ◽  
Daniel Neill ◽  
Mustapha Kandouz
Keyword(s):  
Breast Cancer ◽  
Distant Metastasis ◽  
Predictive Value ◽  
Intracellular Signaling ◽  
Ductal Carcinoma ◽  
Cancer Development ◽  
Eph Receptors ◽  
Free Survival ◽  
Expression Levels ◽  
Ephrin Ligands

Cell–cell communication proteins Eph and ephrin constitute the largest family of receptor tyrosine kinases (RTKs). They are distinguished by the fact that both receptors and ligands are membrane-bound, and both can drive intracellular signaling in their respective cells. Ever since these RTKs have been found to be involved in cancer development, strategies to target them therapeutically have been actively pursued. However, before this goal can be rationally achieved, the contributions of either Eph receptors or their ephrin ligands to cancer development and progression should be scrutinized in depth. To assess the clinical pertinence of this concern, we performed a systematic review and meta-analysis of the prognostic/predictive value of EphB2 and its multiple cognate ephrin ligands in breast cancer. We found that EphB2 has prognostic value, as indicated by the association of higher EphB2 expression levels with lower distant metastasis-free survival (DMFS), and the association of lower EphB2 expression levels with poorer relapse-free survival (RFS). We also found that higher EphB2 expression could be a prognostic factor for distant metastasis, specifically in the luminal subtypes of breast cancer. EFNB2 showed a marked correlation between higher expression levels and shorter DMFS. EFNA5 or EFNB1 overexpression is correlated with longer RFS. Increased EFNB1 expression is correlated with longer OS in lymph node (LN)-negative patients and the luminal B subtype. Higher levels of EFNB2 or EFNA5 are significantly correlated with shorter RFS, regardless of LN status. However, while this correlation with shorter RFS is true for EFNB2 in all subtypes except basal, it is also true for EFNA5 in all subtypes except HER2+. The analysis also points to possible predictive value for EphB2. In systemically treated patients who have undergone either endocrine therapy or chemotherapy, we found that higher expression of EphB2 is correlated with better rates of RFS. Bearing in mind the limitations inherent to any mRNA-based profiling method, we complemented our analysis with an immunohistochemical assessment of expression levels of both the EphB2 receptor and cognate ephrin ligands. We found that the latter are significantly more expressed in cancers than in normal tissues, and even more so in invasive and metastatic samples than in ductal carcinoma in situ (DCIS). Finally, in an in vitro cellular model of breast cancer progression, based on H-Ras-transformation of the MCF10A benign mammary cell line, we observed dramatic increases in the mRNA expression of EphB2 receptor and EFNB1 and EFNB2 ligands in transformed and invasive cells in comparison with their benign counterparts. Taken together, these data show the clinical validity of a model whereby EphB2, along with its cognate ephrin ligands, have dual anti- and pro-tumor progression effects. In so doing, they reinforce the necessity of further biological investigations into Ephs and ephrins, prior to using them in targeted therapies.

Multicenter Validation of a Gene Expression–Based Prognostic Signature in Lymph Node–Negative Primary Breast Cancer

2006 ◽  
Vol 24 (11) ◽  
pp. 1665-1671 ◽  
Author(s):  
John A. Foekens ◽  
David Atkins ◽  
Yi Zhang ◽  
Fred C.G.J. Sweep ◽  
Nadia Harbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Distant Metastasis ◽  
Gene Signature ◽  
Breast Cancer Patients ◽  
Prognostic Signature ◽  
Free Survival ◽  
Node Negative ◽  
Distant Metastasis Free Survival ◽  
Multicenter Validation

Purpose We previously identified in a single-center study a 76-gene prognostic signature for lymph node-negative (LNN) breast cancer patients. The aim of this study was to validate this gene signature in an independent more diverse population of LNN patients from multiple institutions. Patients and Methods Using custom-designed DNA chips we analyzed the expression of the 76 genes in RNA of frozen tumor samples from 180 LNN patients who did not receive adjuvant systemic treatment. Results In this independent validation, the 76-gene signature was highly informative in identifying patients with distant metastasis within 5 years (hazard ratio, [HR], 7.41; 95% CI, 2.63 to 20.9), even when corrected for traditional prognostic factors in multivariate analysis (HR, 11.36; 95% CI, 2.67 to 48.4). The actuarial 5- and 10-year distant metastasis-free survival were 96% (95% CI, 89% to 99%) and 94% (95% CI, 83% to 98%), respectively, for the good profile group and 74% (95% CI, 64% to 81%) and 65% (53% to 74%), respectively for the poor profile group. The sensitivity for 5-yr distant metastasis-free survival was 90%, and the specificity was 50%. The positive and negative predictive values were 38% (95% CI, 29% to 47%) and 94% (95% CI, 86% to 97%), respectively. The 76-gene signature was confirmed as a strong prognostic factor in subgroups of estrogen receptor-positive patients, pre- and postmenopausal patients, and patients with tumor sizes 20 mm or smaller. The subgroup of patients with estrogen receptor-negative tumors was considered too small to perform a separate analysis. Conclusion Our data provide a strong methodologic and clinical multicenter validation of the predefined prognostic 76-gene signature in LNN breast cancer patients.

Introducing a new scoring system based on HER2/neu, p53 oncogenes results and mammographic findings for prediction of tumor grade in breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10687-10687
Author(s):  
M. Guity ◽  
M. Mokri ◽  
M. Shakiba ◽  
M. Atri
Keyword(s):  
Breast Cancer ◽  
Invasive Ductal Carcinoma ◽  
Predictive Value ◽  
Scoring System ◽  
Ductal Carcinoma ◽  
Tumor Grade ◽  
High Grade ◽  
Group Iii ◽  
Immunohistochemical Studies ◽  
New Scoring

10687 Background: During recent years, several oncogenes have been introduced in relation to breast cancer including her2 and P53. These are related with initiation, degree of progression, invasion and prognosis of breast cancer. In this research the rate of positivity of these oncogenes in 150 patients with invasive ductal carcinoma is introduced and the correlation of the results of a new scoring system comprised of mammograms, P53 and her2 with the tumor grade is assessed. Methods: 150 cases of invasive ductal carcinoma of a private clinic were chosen. The diagnosis of cancer and its grade was confirmed by pathology. All patients underwent mammography befor surgery and the results were classified according to BIRADS system to benign (groups of I and II in BIRADS): Score I, suspicious (group III in BIRADS): Score II and malignant (groups of IV and V in BIRADS): score III. P53 and her2 presence were assessed by immunohistochemical studies and the results were classified as negative (score I) and positive (score II). The final score of each patients was calculated by adding scores of all three studies (P53, her2, mammography) which ranged between 3 to 7. Results: The average age of the patients was 48.2 + 11.2 years; most of them were between 30–50 years old. Three had benign mammograms (2%), 81 had suspicious (54%) and 66 had malignant findings (44%). We showed positive P53in 59 (39%), positive her2 in 69 (46%) and high grade tumor in 77 (51%) patients. On scoring, 2 patients gained 3 (1.3%), 36 scored 4 (24%), 53 patients received 5 (35.3%), 37 reached 6 scores (24.7%) and 22 patients received 7 scores (14.7%). Placing scores 3 and 4 in one group and scores 5–7 in another, the sensitivity and negative predictive value of the system for high grade tumors reached 97.7% and 89.5% respectively. By placing scores 3–6 in one group and score 7 in another, the specificity and positive predictive value of the system reached to 100%. Conclusions: The results of mammography, P53 and her2 seems to have a good correlation with tumor grade, meaning when all three parameters are positive, the patients’ tumor is almost always high grade. No significant financial relationships to disclose.

Development of phenotypic indexes for the description of morphological injury in breast cancer cell mitochondria

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22055-e22055
Author(s):  
L. Putignani ◽  
S. Raffa ◽  
R. Pescosolido ◽  
F. Signore ◽  
D. Menichella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cell Biology ◽  
Structural Damage ◽  
Ductal Carcinoma ◽  
Mitochondrial Damage ◽  
Complex Iii ◽  
Protein Fluorescence ◽  
Expression Levels

e22055 Background: Mitochondriopathy has been recently rekindled as new cancer theory. We report on structural damage of breast-infiltrating ductal carcinoma (IDC) mitochondria characterised by reduced expression levels of the oxidative phosphorylation system (OXPHOS). Methods: Mitochondria from HMC-1 (human mammary carcinoma) and HMEC (human mammary epithelial cell) cultures, traced by Mitotracker, were assayed for OXPHOS expression levels using cryo-immunoelectron microscopy (CIEM) quantitative labelling and fluorescence immunolabelling on unfractionated HMC-1 and HEMC cells. Convolution degeneration was established by transmission electron microscopy (TEM). Twenty different cell sections for both HMC-1 and HEMC cells, including 65 and 72 mitochondria, respectively, were randomly recorded and quantitatively analyzed for the percentage of area occupied by intact cristae to provide a grading of mitochondrial damage (cristae loss index). Results: Depressed expression levels were detected for all HMC-1 OXPHOS complexes by CIEM. Normalized labelling density (HEMC/HMC-1), expressed as colloidal gold particles/mitochondrial area (ρ) provided the following values: 1.77 for the NADH-ubiquinone oxidoreductase complex I NDUFS3; 1.86 for the succinate- dehydrogenase complex II SDH-B protein; 1.63 for the ubiquinol cytochrome c reductase complex III UQCRC2; 4.88 and 1.58 for the cytochrome-oxidase complex IV (CO) subunit I and IV, respectively; 2.70 for the ATP-synthase complex V F1β protein. Fluorescence immunolabelling confirmed CIEM quantitative data. MitoTracker's co-staining showed altered membrane potential and permeability. Injury grading was categorised assigning three levels of morphological damage: i) severe, ii) moderate, iii) slight, corresponding to 0 % (6.2 % and 1.4 % for HMC-1 and HMEC, respectively), 1–50 % (21.5 % and 2.8 % for HMC-1 and HMEC, respectively) and 51–75 % (44.6 % and 15.3 % for HMC-1 and HMEC, respectively) of area occupied by intact cristae (p<0.0001, χ2Test). The entire HMC-1 mitochondrial damage resulted 3.7 times higher than that observed for HMEC cells (72.3HMC-1 %/19.5HMEC %). Conclusions: New phenotypic harm indexes for IDC cell mitochondria might provide new hallmarks in breast cancer cell biology. No significant financial relationships to disclose.

HOXB13-to-IL17BR Expression Ratio Is Related With Tumor Aggressiveness and Response to Tamoxifen of Recurrent Breast Cancer: A Retrospective Study

2007 ◽  
Vol 25 (6) ◽  
pp. 662-668 ◽  
Author(s):  
Maurice P.H.M. Jansen ◽  
Anieta M. Sieuwerts ◽  
Maxime P. Look ◽  
Kirsten Ritstier ◽  
Marion E. Meijer-van Gelder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Recurrent Breast Cancer ◽  
Tamoxifen Therapy ◽  
Tumor Aggressiveness ◽  
Expression Ratio ◽  
Free Survival ◽  
Expression Levels ◽  
Er Positive ◽  
Recurrent Breast

Purpose A HOXB13-to-IL17BR expression ratio was previously identified to predict clinical outcome of breast cancer patients treated with adjuvant tamoxifen. However, this ratio may predict a tumor's response to tamoxifen, its intrinsic aggressiveness, or both. Patients and Methods We have measured the HOXB13 and IL17BR expression levels by real-time polymerase chain reaction in 1,252 primary breast tumor specimens. Expression levels were normalized to housekeeper gene levels and related to clinicopathologic factors for all patients. The primary objective of this study was to determine the relationship of a HOXB13-to-IL17BR ratio with tumor aggressiveness and/or with response to tamoxifen therapy in estrogen receptor (ER) -positive disease. We selected ER-positive tumors, and clinical end points for the HOXB13-to-IL17BR ratio were disease-free survival (DFS) in patients with primary breast cancer (N = 619) and progression-free survival (PFS) in patients with recurrent breast cancer treated with first-line tamoxifen monotherapy (N = 193). The odds ratio (OR) and hazard ratio (HR) and their 95% CI were calculated, and all P values were two-sided. Results The HOXB13-to-IL17BR ratio was significantly associated with DFS and PFS. In multivariate analysis, HOXB13-to-IL17BR ratio expression levels were associated with a shorter DFS for node-negative patients only. Corrected for traditional predictive factors, the dichotomized HOXB13-to-IL17BR ratio was the strongest predictor in multivariate analysis for a poor response to tamoxifen therapy (OR = 0.16; 95% CI, 0.06 to 0.45; P < .001) and a shorter PFS (HR = 2.97; 95% CI, 1.82 to 4.86; P < .001). Conclusion High HOXB13-to-IL17BR ratio expression levels associate with both tumor aggressiveness and tamoxifen therapy failure.

scholarly journals Role of miR-10b-5p in the prognosis of breast cancer

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7728 ◽  
Author(s):  
Junmin Wang ◽  
Yanyun Yan ◽  
Zhiqi Zhang ◽  
Yali Li
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Cancer Development ◽  
Clinicopathological Parameters ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Ppi Networks

Breast cancer is the leading cause of cancer-related death in women worldwide. Aberrant expression levels of miR-10b-5p in breast cancer has been reported while the molecular mechanism of miR-10b-5p in tumorigenesis remains elusive. Therefore, this study was aimed to investigate the role of miR-10b-5p in breast cancer and the network of its target genes using bioinformatics analysis. In this study, the expression profiles and prognostic value of miR-10b-5p in breast cancer were analyzed from public databases. Association between miR-10b-5p and clinicopathological parameters were analyzed by non-parametric test. Moreover, the optimal target genes of miR-10b-5p were obtained and their expression patterns were examined using starBase and HPA database. Additionally, the role of these target genes in cancer development were explored via Cancer Hallmarks Analytics Tool (CHAT). The protein–protein interaction (PPI) networks were constructed to further investigate the interactive relationships among these genes. Furthermore, GO, KEGG pathway and Reactome pathway analyses were carried out to decipher functions of these target genes. Results demonstrated that miR-10b-5p was down-regulated in breast cancer and low expression of miR-10b-5p was significantly correlated to worse outcome. Five genes, BIRC5, E2F2, KIF2C, FOXM1, and MCM5, were considered as potential key target genes of miR-10b-5p. As expected, higher expression levels of these genes were observed in breast cancer tissues than in normal tissues. Moreover, analysis from CHAT revealed that these genes were mainly involved in sustaining proliferative signaling in cancer development. In addition, PPI networks analysis revealed strong interactions between target genes. GO, KEGG, and Reactome pathway analysis suggested that these target genes of miR-10b-5p in breast cancer were significantly involved in cell cycle. Predicted target genes were further validated by qRT-PCR analysis in human breast cancer cell line MDA-MB-231 transfected with miR-10b mimic or antisense inhibitors. Taken together, our data suggest that miR-10b-5p functions to impede breast carcinoma progression via regulation of its key target genes and hopefully serves as a potential diagnostic and prognostic marker for breast cancer.

scholarly journals Sharp Downregulation of Hub Genes Associated With the Pathogenesis of Breast Cancer From Ductal Carcinoma In Situ to Invasive Ductal Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yao Wang ◽  
Faqing Liang ◽  
Yuting Zhou ◽  
Juanjuan Qiu ◽  
Qing Lv ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Invasive Ductal Carcinoma ◽  
Ductal Carcinoma ◽  
Cancer Tissue ◽  
Hub Genes ◽  
Expression Levels ◽  
Cancer Pathogenesis ◽  
Ductal Hyperplasia

IntroductionBreast atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are precursor stages of invasive ductal carcinoma (IDC). This study aimed to investigate the pathogenesis of breast cancer by dynamically analyzing expression changes of hub genes from normal mammary epithelium (NME) to simple ductal hyperplasia (SH), ADH, DCIS, and finally to IDC.MethodsLaser-capture microdissection (LCM) data for NME, SH, ADH, DCIS, and IDC cells were obtained. Weighted gene co-expression network analysis (WGCNA) was performed to dynamically analyze the gene modules and hub genes associated with the pathogenesis of breast cancer. Tissue microarray, immunohistochemical, and western blot analyses were performed to determine the protein expression trends of hub genes.ResultsTwo modules showed a trend of increasing expression during the development of breast disease from NME to DCIS, whereas a third module displayed a completely different trend. Interestingly, the three modules displayed inverse trends from DCIS to IDC compared with from NME to DCIS; that is, previously upregulated modules were subsequently downregulated and vice versa. We further analyzed the module that was most closely associated with DCIS (p=7e−07). Kyoto Gene and Genomic Gene Encyclopedia enrichment analysis revealed that the genes in this module were closely related to the cell cycle (p= 4.3e–12). WGCNA revealed eight hub genes in the module, namely, CDK1, NUSAP1, CEP55, TOP2A, MELK, PBK, RRM2, and MAD2L1. Subsequent analysis of these hub genes revealed that their expression levels were lower in IDC tissues than in DCIS tissues, consistent with the expression trend of the module. The protein expression levels of five of the hub genes gradually increased from NME to DCIS and then decreased in IDC. Survival analysis predicted poor survival among breast cancer patients if these hub genes were not downregulated from DCIS to IDC.ConclusionsFive hub genes, RRM2, TOP2A, PBK, MELK, and NUSAP1, which are associated with breast cancer pathogenesis, are gradually upregulated from NME to DCIS and then downregulated in IDC. If these hub genes are not downregulated from DCIS to IDC, patient survival is compromised. However, the underlying mechanisms warrant further elucidation in future studies.

scholarly journals Evaluation of ATOX1 as a Potential Predictive Biomarker for Tetrathiomolybdate Treatment of Breast Cancer Patients with High Risk of Recurrence

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1887
Author(s):  
Stéphanie Blockhuys ◽  
Camilla Hildesjö ◽  
Hans Olsson ◽  
Linda Vahdat ◽  
Pernilla Wittung-Stafshede
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
High Risk ◽  
Cancer Patients ◽  
Phase Ii ◽  
Predictive Biomarker ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Expression Levels

Copper plays a key role in cancer metastasis, which is the most common cause of cancer death. Copper depletion treatment with tetrathiomolybdate (TM) improved disease-free survival in breast cancer patients with high risk of recurrence in a phase II clinical trial. Because the copper metallochaperone ATOX1 was recently reported to drive breast cancer cell migration and breast cancer migration is a critical factor in metastasis, we tested if ATOX1 expression levels in primary tumor tissue could predict the TM treatment outcome of breast cancer patients at high risk of recurrence. We performed ATOX1 immunohistochemical staining of breast tumor material (before TM treatment) of 47 patients enrolled in the phase II TM clinical trial and evaluated ATOX1 expression levels in relation with patient outcome after TM treatment. Our results show that higher ATOX1 levels in the tumor cell cytoplasm correlate with a trend towards better event-free survival after TM treatment for triple-negative breast cancer patients and patients at stage III of disease. In conclusion, ATOX1 may be a potential predictive biomarker for TM treatment of breast cancer patients at high risk of recurrence and should be tested in a larger cohort of patients.

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