Targeting glutamine metabolism enhances responses to platinum-based chemotherapy in triple-negative breast cancers (TNBC).
Ontology highlight
ABSTRACT:
SUBMITTER: Hong J
PROVIDER: S-EPMC9485268 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
Publications
Targeting glutamine metabolism enhances responses to platinum-based chemotherapy in triple-negative breast cancers (TNBC).
Hong Jiaxin J Shen Yao-An YA Hsu Chih-Yi CY Huang Peng P Tomaszewski Alicja A Gabrielson Edward E Shih Ie-Ming IM Gaillard Stephanie S Wang Tian-Li TL
Genes & diseases 20220321 6
Similar Datasets
Project description: Not available
| S-EPMC10486188 | biostudies-literature
Project description:The mechanisms behind drug resistance and sensitivity in breast cancers relies on complex signalling pathways that involve the up or downregulation of certain genes. Many of these genes are involved in adhesion, growth, epithelial/mesenchymal transitions, and apoptosis. We used microarrays to assess differences in gene expression in triple-negative breast cancer cells in response to treatment. We examined the triple-negative human cell line HCC1806 treated with docetaxel or control DMSO. The purpose is to find out the early drug induced changes in this cell line.
2015-07-10 | E-GEOD-70690 | biostudies-arrayexpress
Project description:BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.MethodsIn this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.ResultsWe found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.ConclusionsHence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.
| S-EPMC10507177 | biostudies-literature
Project description:Treatment of triple negative breast cancer (TNBC) has been a big challenge since it is defined. To date, platinum-based chemotherapy has played a significant role in the treatment of TNBC patients. However, some patients do not respond to platinum salts or gradually develop chemoresistance, resulting in little effect, or even some adverse effects. Here, we review numerous preclinical and clinical investigations to summarize possible mechanisms and potential predictive biomarkers of platinum in TNBC. The homologous recombination deficiency (HRD) resulting from the loss of BRCA function is the main rationale of platinum efficacy in TNBC. BRCA mutation and methylation have been demonstrated to be important potential biomarkers. Based on genome-wide effects, BRCA-like classifier can identify the functional loss of BRCA and work as the predictor. HRD score that is able to identify the "BRCAness" and predict the sensitivity of platinum is increasingly considered. Taken together, all findings suggest that HR deficiency profile encompassed by BRCA mutation and high HRD score could predict response to platinum, even to other DNA-damage inducing agents. p53 family members and molecular subtypes of TNBC are also important alternative considerations for predicting platinum response based on the preclinical trials. Currently, tumor infiltrating lymphocyte level and thrombocytopenia are emerging as predictive biomarkers.
| S-EPMC5536940 | biostudies-literature
Project description:The mechanisms behind drug resistance and sensitivity in breast cancers relies on complex signalling pathways that involve the up or downregulation of certain genes. Many of these genes are involved in adhesion, growth, epithelial/mesenchymal transitions, and apoptosis. We used microarrays to assess differences in gene expression in triple-negative breast cancer cells in response to treatment.
2015-07-10 | GSE70690 | GEO
Project description:BackgroundTriple negative breast cancers (TNBC) are associated with an aggressive clinical course, earlier recurrence and short survival. BRCA - mutated tumours represent up to 25% of all TNBC. BRCA status is being studied as a predictive biomarker of response to platinum agents. However, the predictive role of BRCA status is still uncertain in this setting. Since TNBC is a very heterogeneous group of diseases, it is important to identify subsets of TNBC patients that may benefit from platinum-based therapy. This study aims to establish if the presence of a germline BRCA mutation in women with TNBC improves the pathologic complete response (pCR) after neoadjuvant chemotherapy with platinum compounds.MethodsAn extensive literature search was performed in MEDLINE, EMBASE and LILACS databases, WHO (WHO International Clinical Trials Registry Platform) and the Cochrane Controlled Trials Register Database, for online trial registries and conference proceedings. The measurement of pCR was assessed by pathology review of breast specimen and lymph nodes.ResultsThe overall OR was computed using random effects models.Seven studies were included, comprising a total of 808 TNBC patients, among which 159 were BRCA mutated. Among mutated TNBC patients, 93 (93/159; 58.4%) achieved pCR, while 410 wildtype patients (410/808; 50.7%) showed pCR (OR 1.459 CI 95% [0.953-2.34] p = 0.082) although this result did not reach statistical significance.ConclusionsThis meta-analysis shows that the addition of platinum to chemotherapy regimens in the neoadjuvant setting increases pCR rate in BRCA - mutated as compared to wild-type TNBC patients. However, this trend did not achieve statistical significance.Trial registrationCRD42018092341.
| S-EPMC6434625 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy.
| S-EPMC8024381 | biostudies-literature
Project description:Aim: Triple negative breast cancer (TNBC) is known as aggressive subtype and have no identified targeted therapies. We examined the relationship of neoadjuvant chemotherapy response to genetic variations of TNBC. Methods: The tumors used in this study were collected from Showa University Hospital, Japan. Thirteen formalin-fixed paraffin-embedded tumors from Japanese TNBC patients who underwent neoadjuvant chemotherapy were used for analysis. Of these, eight surgically resected tumors showed progressive disease and/or recurrence after treatment (PD/REC), and biopsy tissues from five patients showing pathological complete response (pCR) were analyzed. DNA extracted from tissue sample were analyzed. The Miseq system and Trusight Tumor Sequence panel kit were used to sequence 174 amplicons over 82 exons of 26 cancer-related genes to identify genetic mutations. Results: Seven somatic non-synonymous variants were detected in three genes (FOXL2, PIK3CA, and TP53) in all five pCR patients, and six somatic non-synonymous variants in two genes (PTEN and TP53) were detected in six of eight PD/REC patients. Eight of 13 TNBC tumors were found to have TP53 pathogenic variants, in both pCR and PD/REC cases. Conclusion: Although TP53 variation was detected in both pCR and PD/REC cases, each location and type of the variant were different. We could not identify genetic mutations associated with chemotherapy response and recurrence.
| S-EPMC8992525 | biostudies-literature
Project description:Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER+) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER+ breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER+ cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.
| S-EPMC7492458 | biostudies-literature
Project description:Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their 'basal-like' transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large-scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal-like subtype and inhibited tumor growth in vivo. We employed a multi-omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal-like breast cancer cells. This non-oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies.
| S-EPMC4358660 | biostudies-literature