scholarly journals Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells

2018 ◽  
Vol 399 (7) ◽  
pp. 661-672 ◽  
Author(s):  
Amanda P.B. Albuquerque ◽  
Meritxell Balmaña ◽  
Stefan Mereiter ◽  
Filipe Pinto ◽  
Celso A. Reis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Biology ◽  
Public Health Problem ◽  
Treatment Resistance ◽  
Bioinformatic Analysis ◽  
Serum Deprivation ◽  
Global Public Health ◽  
Advanced Stages

AbstractTriple negative breast cancer (TNBC) is a major global public health problem. The lack of targeted therapy and the elevated mortality evidence the need for better knowledge of the tumor biology. Hypoxia and aberrant glycosylation are associated with advanced stages of malignancy, tumor progression and treatment resistance. Importantly, serum deprivation regulates the invasive phenotype and favors TNBC cell survival. However, in TNBC, the role of hypoxia and serum deprivation in the regulation of glycosylation remains largely unknown. The effects of hypoxia and serum deprivation on the expression of glycosyltransferases and glycan profile were evaluated in the MDA-MB-231 cell line. We showed that the overexpression of HIF-1α was accompanied by acquisition of epithelial-mesenchimal transition features. Significant upregulation of fucosyl- and sialyltransferases involved in the synthesis of tumor-associated carbohydrate antigens was observed together with changes in fucosylation and sialylation detected byAleuria aurantialectin andSambucus nigraagglutinin lectin blots. Bioinformatic analysis further indicated a mechanism by which HIF-1α can regulateST3GAL6expression and the relationship within the intrinsic characteristics of TNBC tumors. In conclusion, our results showed the involvement of hypoxia and serum deprivation in glycosylation profile regulation of TNBC cells triggering breast cancer aggressive features and suggesting glycosylation as a potential diagnostic and therapeutic target.

scholarly journals Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 1 (3) ◽  
pp. 140-147
Author(s):  
Cynthia Villarreal-Garza ◽  
Ana S. Ferrigno ◽  
Alejandro Aranda-Gutierrez ◽  
Paul H. Frankel ◽  
Nora H. Ruel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Point Mutations ◽  
Treatment Resistance ◽  
Cancer Center ◽  
Breast Cancers ◽  
Entire Cohort ◽  
Pathogenic Variants ◽  
Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

scholarly journals Panoptic Overview of Triple-Negative Breast Cancer in Nigeria: Current Challenges and Promising Global Initiatives

2018 ◽  
pp. 1-20
Author(s):  
Nikita Wright ◽  
Padmashree Rida ◽  
Emad Rakha ◽  
Ayodeji Agboola ◽  
Ritu Aneja
Keyword(s):  
Breast Cancer ◽  
United States ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Resource Constraints ◽  
African Ancestry ◽  
Expression Patterns ◽  
Tumor Biology ◽  
The United States ◽  
Nigerian Women

PurposeTriple-negative breast cancer (TNBC) is the most deadly form of breast cancer (BC) today. TNBC treatment is fraught with challenges because of the extensive interpatient heterogeneity in clinical behavior and scarcity of stratifying biomarkers and actionable targets. Women of African ancestry face a disproportionate burden resulting from this disease, which affects them earlier and more aggressively and has a higher propensity to spread and resist conventional treatments. A much higher proportion of Nigerian patients with BC have TNBC compared with patients with BC in the United States and Europe.MethodsThis article spotlights Nigeria as an example of a nation wherein genetic and nongenetic spheres of influence intersect to affect the prevalence of this disease, the scale of its challenge, and its toll.ResultsStudies have illuminated the inherently different tumor biology of Nigerian TNBCs, which show distinct genetic variants and gene expression patterns compared with European or European-American TNBCs. Parallels are apparent between TNBC phenotypes among African Americans and Nigerians, implicating the common thread of shared genetic ancestry between these populations. Reproductive, lifestyle, socioeconomic, and cultural factors also shape TNBC outcomes in Nigeria, as do resource constraints in Nigerian health care and research sectors.ConclusionIncreasing our understanding of how these factors contribute to poorer outcomes among Nigerian women may uncover valuable insights and strategies in alleviating the TNBC burden in many countries of the world and help reduce the racial disparity in BC-related outcomes here in the United States. Importantly, this review also highlights collaborative global and local initiatives that converge expertise and resources to advance research on effective management of TNBC in diverse populations.

scholarly journals Profile and Outcome of Triple Negative Breast Cancer at a Tertiary Care University Hospital in Nepal

2020 ◽  
Vol 5 (2) ◽  
pp. 101-105
Author(s):  
Suman Khanal ◽  
Yogendra P. Singh ◽  
Gita Sayami ◽  
Akihiko Ozaki
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ductal Carcinoma ◽  
Tertiary Care ◽  
Tumor Biology ◽  
Clinical Profile ◽  
University Teaching ◽  
University Hospital ◽  
P Value

Background: TNBC (Triple negative breast cancer) subtype (ER-/PR-/HER2-) of breast cancers are known for aggressive tumor biology and poor survival prospects, with high early relapse rate. However, little is known about the prevalence and characteristics of TNBC breast cancer in Nepal. Objectives: To clarify the geographical distribution, clinical profile and outcome of TNBC patients when compared with non-TNBC patients managed in tertiary care university hospital in Nepal. Materials and Methods: This is a study on prospective observational analyses of TNBC and non-TNBC patients managed at Tribhuvan University Teaching Hospital, Kathmandu from October 2015-March 2018. We collected and analyzed data on clinical profile, pathological tumor features and outcome of the two patient groups. Results: A total of 108 breast cancer patients were included in our study, 38 (35.2%) of which were TNBCs. Mean age at diagnosis was 49±12 years. Majority of TNBCs (29%) were concentrated in Terai districts compared to non-TNBCs (18.6%). Among TNBCs, 15.2% had tumor size 5 cm or more while only 11.9% had such finding in non-TNBCs. Majority of TNBCs and non-TNBCs were of invasive ductal carcinoma of NST histology (76.3 vs 90%). TNBC tumors were significantly of grade 3 (P value=0.003). Perineural invasion was seen more (15.8%) in TNBCs compared to 8.96% in non-TNBCs. On average, 23.6% of total nodes retrieved from axilla were positive for tumor in TNBCs compared to 21% in non-TNBCs. Three patients developed metastases in TNBCs of which two were to brain while 5 had metastases in non-TNBC with none to brain. Higher percentage of patients died in TNBC group (13.2 vs 7.1%). Conclusions: TNBCs are quite common, higher grade tumors with brain metastasis without particular geographic distribution.

scholarly journals Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3145
Author(s):  
Veronica Vella ◽  
Marika Giuliano ◽  
Alessandro La Ferlita ◽  
Michele Pellegrino ◽  
Germano Gaudenzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Insulin Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Biological Effects ◽  
Tumor Biology ◽  
Endogenous Insulin

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.

scholarly journals Overexpression of CCNE1 confers a poorer prognostic in triple negative breast cancer identified by bioinformatic analysis

2020 ◽  
Author(s):  
Qianqian Yuan ◽  
Lewei Zheng ◽  
Yiqin Liao ◽  
Gaosong Wu
Keyword(s):  
Breast Cancer ◽  
Survival Analysis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Cancer Survival ◽  
Process Analysis ◽  
Interaction Network ◽  
Bioinformatic Analysis ◽  
Gene Expression Omnibus

Abstract Background. Triple-negative breast cancer (TNBC) is a major subtype of breast cancer. Due to the lack of effective therapeutic targets, the prognosis is poor. In order to find an effective target, despite many efforts, the molecular mechanisms of TNBC are still not well understood which remain to be a profound clinical challenge.Methods. To identify the candidate genes in the carcinogenesis and progression of TNBC, microarray datasets GSE36693 and GSE65216 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and functional and pathway enrichment analyses were performed using the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) databases via DAVID. We constructed the protein-protein interaction network (PPI) and the performed the module analysis using STRING and Cytoscape. Then we reanalyzed the selected DEGs genes and the survival analysis was performed using cBioportal.Results. A total of 140 DEGs were identified, consisting of 69 upregulated genes and 71 downregulated genes. Three hub genes were up-regulated among the selected genes from PPI and biological process analysis uncovered the fact that these genes were mainly enriched in p53 pathway and the pathways in cancer. Survival analysis showed that only CCNE1 may be involved in the carcinogenesis, invasion or recurrence of TNBC. Conclusion. CCNE1 could confer a poorer prognostic in TNBC identified by bioinformatic analysis and play key roles in the progression of TNBC which may contribute potential targets for the diagnosis, treatment and prognosis assessment of TNBC.

scholarly journals HOX Transcript Antisense RNA HOTAIR Abrogates Vasculogenic Mimicry by Targeting the AngiomiR-204/FAK Axis in Triple Negative Breast Cancer Cells

2020 ◽  
Vol 6 (2) ◽  
pp. 19
Author(s):  
Allan Lozano-Romero ◽  
Horacio Astudillo-de la Vega ◽  
María Cruz del Rocío Terrones-Gurrola ◽  
Laurence A. Marchat ◽  
Daniel Hernández-Sotelo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Bioinformatic Analysis ◽  
Luciferase Reporter ◽  
Reporter Assays

HOX transcript antisense RNA (HOTAIR) is an oncogenic long non-coding RNA frequently overexpressed in cancer. HOTAIR can enhance the malignant behavior of tumors by sponging microRNAs with tumor suppressor functions. Vasculogenic mimicry is a hypoxia-activated process in which tumor cells form three-dimensional (3D) channel-like networks, resembling endothelial blood vessels, to obtain nutrients. However, the role of HOTAIR in vasculogenic mimicry and the underlying mechanisms are unknown in human cancers. In the current study, we investigated the relevance of HOTAIR in hypoxia-induced vasculogenic mimicry in metastatic MDA-MB-231 and invasive Hs-578t triple negative breast cancer cells. Analysis of The Cancer Genome Atlas (TCGA) database using cBioPortal confirmed that HOTAIR was upregulated in clinical breast tumors relative to normal mammary tissues. Our quantitative RT-PCR assays showed a significant increase in HOTAIR levels after 48 h hypoxia relative to normoxia in breast cancer cell lines. Remarkably, knockdown of HOTAIR significantly abolished the hypoxia-induced vasculogenic mimicry which was accompanied by a reduction in the number of 3D channel-like networks and branch points. Likewise, HOTAIR silencing leads to reduced cell migration abilities of cancer cells. Bioinformatic analysis predicted that HOTAIR has a potential binding site for tumor suppressor miR-204. Luciferase reporter assays confirmed that HOTAIR is a competitive endogenous sponge of miR-204. Congruently, forced inhibition of HOTAIR in cells resulted in augmented miR-204 levels in breast cancer cells. Further bioinformatic analysis suggested that miR-204 can bind to the 3′ untranslated region of focal adhesion kinase 1 (FAK) transcript involved in cell migration. Western blot and luciferase reporter assays confirmed that FAK is a novel target of miR-204. Finally, silencing of HOTAIR resulted in low levels of cytoplasmic FAK protein and alterations in the organization of cellular cytoskeleton and focal adhesions. In summary, our results showed, for the first time, that HOTAIR mitigates cell migration and vasculogenic mimicry by targeting the miR-204/FAK axis in triple negative breast cancer cells.

scholarly journals Overexpression of CCNE1 confers a poorer prognosis in triple-negative breast cancer identified by bioinformatic analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qianqian Yuan ◽  
Lewei Zheng ◽  
Yiqin Liao ◽  
Gaosong Wu
Keyword(s):  
Breast Cancer ◽  
Survival Analysis ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Cancer Survival ◽  
Process Analysis ◽  
Interaction Network ◽  
Bioinformatic Analysis ◽  
Gene Expression Omnibus

Abstract Background Triple-negative breast cancer (TNBC) is a major subtype of breast cancer. Due to the lack of effective therapeutic targets, the prognosis is poor. In order to find an effective target, despite many efforts, the molecular mechanisms of TNBC are still not well understood which remain to be a profound clinical challenge. Methods To identify the candidate genes in the carcinogenesis and progression of TNBC, microarray datasets GSE36693 and GSE65216 were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and functional and pathway enrichment analyses were performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases via DAVID. We constructed the protein-protein interaction network (PPI) and performed the module analysis using STRING and Cytoscape. Then, we reanalyzed the selected DEG genes, and the survival analysis was performed using cBioportal. Results A total of 140 DEGs were identified, consisting of 69 upregulated genes and 71 downregulated genes. Three hub genes were upregulated among the selected genes from PPI, and biological process analysis uncovered the fact that these genes were mainly enriched in p53 pathway and the pathways in cancer. Survival analysis showed that only CCNE1 may be involved in the carcinogenesis, invasion, or recurrence of TNBC. The expression levels of CCNE1 were significantly higher in TNBC cells than non-TNBC cells that were detected by qRT-PCR (P < 0.05). Conclusion CCNE1 could confer a poorer prognosis in TNBC identified by bioinformatic analysis and plays key roles in the progression of TNBC which may contribute potential targets for the diagnosis, treatment, and prognosis assessment of TNBC.

scholarly journals PRMT1 Confers Resistance to Olaparib via Modulating MYC Signaling in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 (10) ◽  
pp. 1009
Author(s):  
Wen-Jing Hsu ◽  
Cheng-Hsun Chen ◽  
Yu-Chu Chang ◽  
Chia-Hsiung Cheng ◽  
Ying-Huei TsaI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Protein Stability ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Bioinformatic Analysis ◽  
Parp Inhibitors ◽  
Methyl Transferase

Treatment of triple-negative breast cancer (TNBC) remains an unmet clinical need owing to its lack of an efficient therapeutic target. The targeting of DNA repair by poly(ADP-ribose) polymerase (PARP) inhibitors has shown benefit for patients with the BRCA variation. However, sensitivities to the PARP inhibitors were reported regardless of BRCA status. Thus, exploring the underlying mechanisms is imperative. Herein, we identified that breast cancer cells with an elevated expression of protein arginine methyl transferase 1 (PRMT1) was associated with therapeutic sensitivity to the PARP inhibitor olaparib. The results of cell viability and colony formation assays indicated that the suppression of PRMT1 by small hairpin RNA or by the chemical inhibitor increased sensitivity to olaparib in human TNBC MDA-MB-231 and BT549 cells. Bioinformatic analysis revealed that PRMT1 expression was significantly associated with the MYC signature, and TNBC cells with higher PRMT1 and the MYC signature were associated with therapeutic sensitivity to olaparib. Mechanistic studies further demonstrated that knockdown of PRMT1 reduced the c-Myc protein level and downregulated the expression of MYC downstream targets, whereas overexpression of PRMT1 enhanced c-Myc protein expression. Moreover, the overexpression of PRMT1 promoted c-Myc protein stability, and the inhibition of PRMT1 downregulated c-Myc protein stability. Accordingly, the knockdown of PRMT1 inhibited homologous recombination gene expression. These data indicate that PRMT1 is instrumental in regulating DNA repair, at least in part, by modulating c-Myc signaling. Our data highlighted the PRMT1/c-Myc network as a potential therapeutic target in patients with TNBC.

scholarly journals Immune Milieu and Genomic Alterations Set the Triple-Negative Breast Cancer Immunomodulatory Subtype Tumor Behavior

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6256
Author(s):  
Rubén Rodríguez-Bautista ◽  
Claudia H. Caro-Sánchez ◽  
Paula Cabrera-Galeana ◽  
Gerardo J. Alanis-Funes ◽  
Everardo Gutierrez-Millán ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Dna Sequencing ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Genomic Alterations

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Seven subtypes have been described based on gene expression patterns. Herein, we characterized the tumor biology and clinical behavior of the immunomodulatory (IM) subtype. Methods: Formalin-fixed paraffin-embedded tumor samples from 68 high-risk (stage III-IV) TNBC patients were analyzed through microarrays, immunohistochemistry, and DNA sequencing. Results: The IM subtype was identified in 24% of TNBC tumor samples and characterized by a higher intratumoral (intT) and stromal (strml) infiltration of FOXP3+ TILs (Treg) compared with non-IM subtypes. Further, PD-L1+ (>1%) expression was significantly higher, as well as CTLA-4+ intT and strml expression in the IM subtype. Differential expression and gene set enrichment analysis identified biological processes associated with the immune system. Pathway analysis revealed enrichment of the β-catenin signaling pathway. The non-coding analysis led to seven Long Intergenic Non-Protein Coding RNAs (lincRNAs) (6 up-regulated and 1 down-regulated) that were associated with a favorable prognosis in the TNBC-IM subtype. The DNA sequencing highlighted two genes relevant to immune system responses: CTNNB1 (Catenin β-1) and IDH1. Conclusion: the IM subtype showed a distinct immune microenvironment, as well as subtype-specific genomic alterations. Characterizing TNBC at a molecular and transcriptomic level might guide immune-based therapy in this subgroup of patients.

Sign in / Sign up

Export Citation Format

Share Document