scholarly journals Kallikrein-related peptidases in triple negative breast cancer: prognostic value of quantitatively assessed KLK8, KLK10 and KLK11 mRNA expression

2021 ◽  
Author(s):  
Yueyang Liu ◽  
Sarah Preis ◽  
Geng Xiaocong ◽  
Weiwei Gong ◽  
Marion Kiechle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mrna Expression Levels

Abstract Background. Triple-negative breast cancer (TNBC) is a breast cancer subtype with poor prognosis and limited targeted therapy options. Multiple KLKs have been described to play key roles in carcinogenesis and metastasis of breast cancer. Purpose. In the present study, the clinical significance of KLK8, KLK10, and KLK11 mRNA expression in tumor tissue of TNBC patients was investigated. Methods. The mRNA expression levels of KLK8, 10, and 11 were quantified by quantitative PCR and their prognostic values were analyzed in a large, well-characterized TNBC cohort (n = 123). Results. Significantly positive correlations were observed between all three KLK mRNA levels indicating coordinate expression of these proteases in TNBC. In univariate analyses, both elevated KLK8, KLK10 as well as all combinations of the three factors (KLK8 + KLK10, KLK8 + KLK11, KLK10 + KLK11, KLK8 + KLK10 + KLK11) were significantly associated with shortened disease-free survival (DFS), while high mRNA levels of KLK11, as well as KLK10 + KLK11 were significantly associated with shortened overall survival (OS). In multivariate Cox regression analyses, KLK10 and all combined factors remained unfavorable independent predictive markers for DFS, while high KLK11 mRNA expression represented an unfavorable independent predictor for OS. Conclusions. Increased KLK8, KLK10, and KLK11 mRNA expression levels are associated with unfavorable prognosis in triple-negative breast cancer. The combination of KLK8 + KLK10 + KLK11 may represent a stronger prognostic biomarker for DFS than KLK8, KLK10, KLK11 alone, or other combinations thereof, whereas KLK11 mRNA expression is an independent prognostic biomarker for OS in TNBC patients.

scholarly journals Druggable Nucleolin Identifies Breast Tumours Associated with Poor Prognosis That Exhibit Different Biological Processes

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 390 ◽  
Author(s):  
Flora Nguyen Van Long ◽  
Audrey Lardy-Cleaud ◽  
Susan Bray ◽  
Sylvie Chabaud ◽  
Thierry Dubois ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Expression Profiles ◽  
Disease Free Survival ◽  
Mrna Levels ◽  
Breast Cancers ◽  
Breast Tumours ◽  
Expression Levels ◽  
Cancer Management ◽  
Mrna Expression Levels

Background: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. Anti-NCL drugs show strong cytotoxic effects, including in triple-negative breast cancer (TNBC) models, and are currently being evaluated in phase II clinical trials. However, few studies have investigated the clinical value of NCL and whether NCL stratified cancer patients. Here, we have investigated for the first time the association of NCL with clinical characteristics in breast cancers independently of the different subtypes. Methods: Using two independent series (n = 216; n = 661), we evaluated the prognostic value of NCL in non-metastatic breast cancers using univariate and/or multivariate Cox-regression analyses. Results: We reported that NCL mRNA expression levels are markers of poor survivals independently of tumour size and lymph node invasion status (n = 216). In addition, an association of NCL expression levels with poor survival was observed in TNBC (n = 40, overall survival (OS) p = 0.0287, disease-free survival (DFS) p = 0.0194). Transcriptomic analyses issued from The Cancer Genome Atlas (TCGA) database (n = 661) revealed that breast tumours expressing either low or high NCL mRNA expression levels exhibit different gene expression profiles. These data suggest that tumours expressing high NCL mRNA levels are different from those expressing low NCL mRNA levels. Conclusions: NCL is an independent marker of prognosis in breast cancers. We anticipated that anti-NCL is a promising therapeutic strategy that could rapidly be evaluated in high NCL-expressing tumours to improve breast cancer management.

scholarly journals Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer

2021 ◽  
Vol 28 (5) ◽  
pp. 4080-4092
Author(s):  
Takahiro Ichikawa ◽  
Masahiro Shibata ◽  
Takahiro Inaishi ◽  
Ikumi Soeda ◽  
Mitsuro Kanda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Mrna Expression ◽  
Cell Lines ◽  
Mrna Levels ◽  
Pcr Array ◽  
Array Analysis ◽  
Expression Levels ◽  
Er Positive ◽  
Mrna Expression Levels

Background: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers; however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. Methods: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients’ clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. Results: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. Conclusion: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

scholarly journals High Expression of microRNA-223 Indicates a Good Prognosis in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Li Chen ◽  
Xiuzhi Zhu ◽  
Boyue Han ◽  
Lei Ji ◽  
Ling Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Molecular Subtype ◽  
External Validation ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Locked Nucleic Acid ◽  
Tnbc Subtype

PurposeMicroRNAs can influence many biological processes and have shown promise as cancer biomarkers. Few studies have focused on the expression of microRNA-223 (miR-223) and its precise role in breast cancer (BC). We aimed to examine the expression level of miR-223 and its prognostic value in BC.MethodsTissue microarray (TMA)-based miRNA detection in situ hybridization (ISH) with a locked nucleic acid (LNA) probe was used to detect miR-223 expression in 450 BC tissue samples. Overall survival (OS) and disease-free survival (DFS) were compared between two groups using the Kaplan-Meier method and Cox regression model.ResultsOS and DFS were prolonged in the high miR-223 expression group compared to the low miR-223 expression group (p < 0.0001 and p = 0.017, respectively), especially in patients with the triple-negative breast cancer (TNBC) subtype (p = 0.046 and p < 0.001, respectively). Univariate and multivariate Cox regression analyses revealed that TNM stage (p = 0.008), the molecular subtype (p = 0.049), and miR-223 (p < 0.001) were independently associated with OS and DFS. External validation was performed with the METABRIC and The Cancer Genome Atlas (TCGA) databases via online webtools and was consistent with the data described above.ConclusionsThis study provides evidence that high miR-223 expression at diagnosis is associated with improved DFS and OS for BC patients, especially those with the TNBC subtype. miR-223 is a valid and independent prognostic biomarker in BC.

scholarly journals Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

2019 ◽  
Author(s):  
Teresa Gagliano ◽  
Kalpit Shah ◽  
Sofia Gargani ◽  
Liyan Lao ◽  
Mansour Alsaleem ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Disease Free Survival ◽  
Mrna Levels ◽  
Primary Fibroblasts ◽  
Independent Effects

AbstractAs there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

scholarly journals Simultaneous Quantitative Detection of Relevant Biomarkers in Breast Cancer by Quantitative Real-Time PCR

2006 ◽  
Vol 21 (1) ◽  
pp. 30-39 ◽  
Author(s):  
M. Labuhn ◽  
V. Vuaroqueaux ◽  
F. Fina ◽  
A. Schaller ◽  
I. Nanni-Metellus ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Real Time ◽  
Real Time Pcr ◽  
Quantitative Detection ◽  
Mrna Levels ◽  
Quantitative Real Time Pcr ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Mrna Expression Levels

The assessment of ERα, PgR and HER2 status is routinely performed today to determine the endocrine responsiveness of breast cancer samples. Such determination is usually accomplished by means of immunohistochemistry and in case of HER2 amplification by means of fluorescent in situ hybridization (FISH). The analysis of these markers can be improved by simultaneous measurements using quantitative real-time PCR (Qrt-PCR). In this study we compared Qrt-PCR results for the assessment of mRNA levels of ERα, PgR, and the members of the human epidermal growth factor receptor family, HER1, HER2, HER3 and HER4. The results were obtained in two independent laboratories using two different methods, SYBR Green I and TaqMan probes, and different primers. By linear regression we demonstrated a good concordance for all six markers. The quantitative mRNA expression levels of ERα, PgR and HER2 also strongly correlated with the respective quantitative protein expression levels prospectively detected by EIA in both laboratories. In addition, HER2 mRNA expression levels correlated well with gene amplification detected by FISH in the same biopsies. Our results indicate that both Qrt-PCR methods were robust and sensitive tools for routine diagnostics and consistent with standard methodologies. The developed simultaneous assessment of several biomarkers is fast and labor effective and allows optimization of the clinical decision-making process in breast cancer tissue and/or core biopsies.

scholarly journals Decreased sensitivity of several anticancer drugs in TMEPAI knockout triple-negative breast cancer cells

2019 ◽  
Vol 28 (2) ◽  
pp. 110-5
Author(s):  
Bantari Wisynu Kusuma Wardhani ◽  
Meidi Utami Puteri ◽  
Yukihide Watanabe ◽  
Melva Louisa ◽  
Rianto Setiabudy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Anticancer Drugs ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Expression Levels ◽  
Drug Efflux Transporters

BACKGROUND Transmembrane prostate androgen-induced protein (TMEPAI) was reported to be highly amplified in the majority of patients with triple-negative breast cancer (TNBC). TMEPAI is related to poorer prognosis, limited treatment options, and prone to drug resistance compared with other proteins. One of the established markers to determine cancer resistance to drugs is the increased expression levels of drug efflux transporters. However, the role of TMEPAI in cancer resistance to drugs has not been elucidated. This study was aimed to investigate whether TMEPAI participates in cancer resistance to drugs by regulating drug efflux transporters. METHODS TMEPAI knockout (KO) cells were previously developed from a TNBC cell line, Hs578T (wild-type/WT), using a CRISPR-Cas9 system. The expression levels of drug efflux transporters were determined in Hs578T-KO and Hs578-WT by quantitative reverse transcriptase polymerase chain reaction. Cytotoxic concentration 50% (CC50) of several anticancer drugs (doxorubicin, cisplatin, and paclitaxel) were determined in the two cell lines via 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. RESULTS The results showed that the mRNA expression of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) was significantly increased in Hs578T-KO compared with that in Hs578T-WT cells. CC50 of several anticancer drugs investigated (doxorubicin, paclitaxel, and cisplatin) in Hs578T-KO cells was higher than that in Hs678-WT. CONCLUSIONS TMEPAI participated in the regulation of mRNA expression levels in drug efflux transporters (P-gp, BCRP, and multidrug resistance-associated protein 1). Further studies are necessary to confirm whether this finding might be dependent on the development of cancer cell sensitivity to anticancer agents.

scholarly journals An Immunohistochemical Panel of Three SUMO Genes Predicts Outcomes of Patients With Triple-negative Breast Cancer

2020 ◽  
Author(s):  
Yuxiang Lin ◽  
Qingshui Wang ◽  
Han Xiao ◽  
Zhiwei Chen ◽  
Meichen Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Chemotherapy Response ◽  
Patient Counseling ◽  
Predictive Tool ◽  
Post Translational Modifications ◽  
Response To Chemotherapy

Abstract Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease. Developing new candidate biomarkers for chemotherapy response and possible therapeutic targets has become an urgent clinical need. Small ubiquitin-like modifier (SUMOs) mediate post-translational modifications (SUMOylation) that target multiple proteins was involved in many biological processes. The role of SUMOylation in TNBC remains to be elucidated.Method: The expression of SUMO1/2/3 were analyzed using TCGA and GEO databases (N=412). We also evaluated the SUMO1/2/3 protein expression in 212 local TNBC patients using immunohistochemical (IHC) staining. We then built a classifier with the LASSO Cox regression model based on associations between the expression of SUMO1/2/3 proteins and the disease-free survival (DFS) of TNBC patients. Results: Elevated SUMO1/2/3 levels were indicated to be associated with a poorer overall survival (OS) and DFS for TNBC patients. Using the LASSO model, we built a classifier based on the IHC scores of SUMO1/2/3 proteins and named it ‘SB classifier’. Patients with the SB classifier defined high score were found to have an unfavorable response to chemotherapy (HR 4.04, 2.14-7.63; p<0.0001). We then developed a nomogram to predict which patients might benefit from chemotherapy. Finally, our analysis provides insights on possible mechanisms that MYC activation causes the activation of SUMOylation. Conclusion: We constructed a reliable prognostic and predictive tool for TNBC patients treated with chemotherapy. It may facilitate patient counseling and individualize management of TNBC patients. Meanwhile, our results suggested that the activation of SUMOylation pathway in TNBC may be induced by MYC signaling.

scholarly journals Exploring the metastatic role of the inhibitor of apoptosis BIRC6 in Breast Cancer

2021 ◽  
Author(s):  
Santiago Manuel Gomez Bergna ◽  
Abril Marchesini ◽  
Leslie Cinthya Amoros Morales ◽  
Paula Nazarena Arrias ◽  
Hernan Gabriel Farina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Ontology ◽  
Mrna Expression ◽  
Differential Expression ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Expression Levels ◽  
Apoptosis Protein ◽  
Mrna Expression Levels

Breast cancer is the most common cancer as well as the first cause of death by cancer in women worldwide. BIRC6 (baculoviral IAP repeat-containing protein 6) is a member of the inhibitors of apoptosis protein family thought to play an important role in the progression or chemoresistance of many cancers. The aim of the present work was to investigate the role of apoptosis inhibitor BIRC6 in breast cancer, focusing particularly on its involvement in the metastatic cascade. We analyzed BIRC6 mRNA expression levels and Copy Number Variations (CNV) in three breast cancer databases from The Cancer Genome Atlas (TCGA) comparing clinical and molecular attributes. Genomic analysis was performed using CBioportal platform while transcriptomic studies (mRNA expression levels, correlation heatmaps, survival plots and Gene Ontology) were performed with USC Xena and R. Statistical significance was set at p values less than 0.05. Our analyses showed that there was a differential expression of BIRC6 in cancer samples when compared to normal samples. CNV that involve amplification and gain of BIRC6 gene were correlated with negative hormone receptor tumors, higher prognostic indexes, younger age at diagnosis and both chemotherapy and radiotherapy administration. Transcriptomic and gene-ontology analyses showed that, in conditions of high BIRC6 mRNA levels, there are differential expression patterns in apoptotic, proliferation, and metastatic pathways. In summary, our in silico analyses suggest that BIRC6 exhibits an antiapoptotic, pro-proliferative and an apparent pro-metastatic role and could be a relevant molecular target for treatment of Breast Cancer tumors.

scholarly journals Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial

2019 ◽  
Vol 37 (36) ◽  
pp. 3484-3492 ◽  
Author(s):  
Priyanka Sharma ◽  
William E. Barlow ◽  
Andrew K. Godwin ◽  
Eileen E. Parkes ◽  
Laura A. Knight ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes

PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated ( r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

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