Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas

2021 ◽  
Author(s):  
Omkar B Ijare ◽  
Shashank Hambarde ◽  
Fabio Henrique Brasil da Costa ◽  
Sophie Lopez ◽  
Martyn A Sharpe ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Acid Biosynthesis ◽  
Tumor Tissues ◽  
Metabolite Profiles ◽  
Human Meningiomas ◽  
Grade Ii ◽  
Nonessential Amino Acids ◽  
Tracer Experiments

Abstract Background We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unravelling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. Methods 1H NMR spectroscopy of tumor tissues from 33 meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/ 15N glutamine tracer, in five patient-derived meningioma cells. Results Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75% and 33% respectively, with alanine, and glutamine being statistically significant (p ≤ 0.02). 13C/ 15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. Conclusion Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) would be very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.

Calreticulin is Differentially Expressed in Invasive Ductal Carcinoma: A Comparative Study

2019 ◽  
Vol 16 (2) ◽  
pp. 148-155
Author(s):  
Asma Tariq ◽  
Rana Muhammad Mateen ◽  
Iram Fatima ◽  
Muhammad Waheed Akhtar
Keyword(s):  
Invasive Ductal Carcinoma ◽  
Tumor Tissue ◽  
Ductal Carcinoma ◽  
Tissue Level ◽  
Differentially Expressed ◽  
Breast Cancer Patients ◽  
Two Dimensional Gel Electrophoresis ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Grade Ii

Objective: The aim of the present study was to build protein profiles of untreated breast cancer patients of invasive ductal carcinoma grade II at tissue level in Pakistani population and to compare 2-D profiles of breast tumor tissues with matched normal tissues in order to evaluate for variations of proteins among them. Materials & Methods: Breast tissue profiles were made after polytron tissue lysis and rehydrated proteins were further characterized by using two-dimensional gel electrophoresis. On the basis of isoelectric point (pI) and molecular weight, proteins were identified by online tool named Siena 2-D database and their identification was further confirmed by using MALDI-TOF. Results: Among identified spots, 10 proteins were found to be differentially expressed i.e.; COX5A, THIO, TCTP, HPT, SODC, PPIA, calreticulin (CRT), HBB, albumin and serotransferrin. For further investigation, CRT was selected. The level of CRT in tumors was found to be significantly higher than in normal group (p < 0.05). The increased expression of CRT level in tumor was statistically significant (p = 0.010) at a 95% confidence level (p < 0.05) as analyzed by Mann-Whitney. CRT was found distinctly expressed in high amount in tumor tissue as compared to their matched normal tissues. Conclusion: It has been concluded that CRT expression could discriminate between normal tissue and tumor tissue so it might serve as a possible candidate for future studies in cancer diagnostic markers.

scholarly journals Validation of MicroRNA-188-5p Inhibition Power on Tumor Cell Proliferation in Papillary Thyroid Carcinoma

2020 ◽  
Vol 29 ◽  
pp. 096368972091830 ◽  
Author(s):  
Ping Zhou ◽  
Andrew Irving ◽  
Huifang Wu ◽  
Juan Luo ◽  
Johana Aguirre ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Tumor Cell ◽  
Cellular Proliferation ◽  
Tumor Cell Proliferation ◽  
Papillary Thyroid ◽  
Tumor Tissues ◽  
Potential Biomarker ◽  
And Function

Given the crucial role of microRNAs in the cellular proliferation of various types of cancers, we aimed to analyze the expression and function of a cellular proliferation-associated miR-188-5p in papillary thyroid carcinoma (PTC). Here we demonstrate that miR-188-5p is downregulated in PTC tumor tissues compared with the associated noncancerous tissues. We also validate that the miR-188-5p overexpression suppressed the PTC cancer cell proliferation. In addition, fibroblast growth factor 5 (FGF5) is observed to be downregulated in the PTC tumor tissues compared with the associated noncancerous tissues. Subsequently, FGF5 is identified as the direct functional target of miR-188-5p. Moreover, the silencing of FGF5 was found to inhibit PTC cell proliferation, which is the same pattern as miR-188-5p overexpression. These results suggest that miR-188-5p-associated silencing of FGF5 inhibits tumor cell proliferation in PTC. It also highlights the importance of further evaluating miR-188-5p as a potential biomarker and therapy target in PTC.

scholarly journals Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 447 ◽  
Author(s):  
Hayato Nakagawa ◽  
Yuki Hayata ◽  
Satoshi Kawamura ◽  
Tomoharu Yamada ◽  
Naoto Fujiwara ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hepatocellular Carcinoma ◽  
Local Environment ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Metabolic Alterations ◽  
Rich Condition ◽  
Visceral Adipose ◽  
Hcc Cells

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.

scholarly journals The Expression of miR-513c and miR-3163 was Downregulated in Tumor Tissues Compared with Margin Tissues of Patients With Breast Cancer

2020 ◽  
Author(s):  
Soheila Delgir ◽  
Khandan Ilkhani ◽  
Asma Safi ◽  
Farhad Seif ◽  
Milad Bastami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
In Silico ◽  
In Silico Analysis ◽  
Glutamine Metabolism ◽  
Expression Level ◽  
P Value ◽  
Biological Processes ◽  
Tumor Tissues ◽  
Silico Analysis

Abstract Background Breast cancer (BC) is the most common invasive cancer with different subtypes that its metabolism is unique compared with normal cells. Glutamine is considered a critical nutrition for tumor cell growth and therefore, targeting glutamine metabolism, especially Glutaminase, which catalyzed the conversion of glutamine to glutamate can be beneficial to design anti-cancer agents. Recently, evidence has shown that miRNAs with short length and single strand properties play a significant role in regulating the genes related to glutamine metabolism and may control the development of cancer.Methods Since, in-silico analysis confirmed that miR-513c and miR-3163 might be involved in glutamine metabolism, the expression level of these two miRNAs was evaluated in eighty BC tissues and margin tissues. The data were analyzed to evaluate the correlation between expression level of these miRNAs and patient’s characteristics such as abortion history, family history, and age. Furthermore, in-silico analysis was applied to predict the potential biological processes and molecular pathways of miR-513c and miR-3163 based on its gene targets.Results In-silico studies revealed the top categories of biological processes and pathways that play a critical role in cancer development were target genes for miR-513c and miR-3163. The current study showed that miR-513c (P-value = 0.02062 and fold change= -2.3801) and miR-3163 (P-value = 0.02034 and fold change= -2.3792) were downregulated in tumor tissues compared to margin tissues. Furthermore, the subgroup studies did not show any substantial relationship between expression levels of these two miRNAs and factors such as age, family history cancer, and abortion.Conclusion Based on our data, miR-513c and miR-3163 may be offered as a potential diagnosis and therapeutic targets for patients with BC.

STK11/TP53 co-mutated non-small cell lung cancer (NSCLC) to display a unique tumor microenvironment (TME) and metabolic profile.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9087-9087
Author(s):  
Abdul Rafeh Naqash ◽  
Charalampos S. Floudas ◽  
Asaf Maoz ◽  
Joanne Xiu ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hierarchical Clustering ◽  
Immune Cell ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Content

9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.

scholarly journals Spatially resolved metabolomics to discover tumor-associated metabolic alterations

2018 ◽  
Vol 116 (1) ◽  
pp. 52-57 ◽  
Author(s):  
Chenglong Sun ◽  
Tiegang Li ◽  
Xiaowei Song ◽  
Luojiao Huang ◽  
Qingce Zang ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Fatty Acid Biosynthesis ◽  
Spatial Information ◽  
Tumor Therapy ◽  
Metabolic Enzymes ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Ionization Mass ◽  
Metabolic Alterations ◽  
Spatially Resolved

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

scholarly journals Oncogenic Metabolism Acts as a Prerequisite Step for Induction of Cancer Metastasis and Cancer Stem Cell Phenotype

2018 ◽  
Vol 2018 ◽  
pp. 1-28 ◽  
Author(s):  
Su Yeon Lee ◽  
Min Kyung Ju ◽  
Hyun Min Jeon ◽  
Yig Ji Lee ◽  
Cho Hee Kim ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cell ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Cell Phenotype ◽  
Mesenchymal Transition

Metastasis is a major obstacle to the efficient and successful treatment of cancer. Initiation of metastasis requires epithelial-mesenchymal transition (EMT) that is regulated by several transcription factors, including Snail and ZEB1/2. EMT is closely linked to the acquisition of cancer stem cell (CSC) properties and chemoresistance, which contribute to tumor malignancy. Tumor suppressor p53 inhibits EMT and metastasis by negatively regulating several EMT-inducing transcription factors and regulatory molecules; thus, its inhibition is crucial in EMT, invasion, metastasis, and stemness. Metabolic alterations are another hallmark of cancer. Most cancer cells are more dependent on glycolysis than on mitochondrial oxidative phosphorylation for their energy production, even in the presence of oxygen. Cancer cells enhance other oncogenic metabolic pathways, such as glutamine metabolism, pentose phosphate pathway, and the synthesis of fatty acids and cholesterol. Metabolic reprogramming in cancer is regulated by the activation of oncogenes or loss of tumor suppressors that contribute to tumor progression. Oncogenic metabolism has been recently linked closely with the induction of EMT or CSC phenotypes by the induction of several metabolic enzyme genes. In addition, several transcription factors and molecules involved in EMT or CSCs, including Snail, Dlx-2, HIF-1α, STAT3, TGF-β, Wnt, and Akt, regulate oncogenic metabolism. Moreover, p53 induces metabolic change by directly regulating several metabolic enzymes. The collective data indicate the importance of oncogenic metabolism in the regulation of EMT, cell invasion and metastasis, and adoption of the CSC phenotype, which all contribute to malignant transformation and tumor development. In this review, we highlight the oncogenic metabolism as a key regulator of EMT and CSC, which is related with tumor progression involving metastasis and chemoresistance. Targeting oncometabolism might be a promising strategy for the development of effective anticancer therapy.

scholarly journals Comparative Metabolomics of Early Development of the Parasitic Plants Phelipanche aegyptiaca and Triphysaria versicolor

Metabolites ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 114 ◽  
Author(s):  
Kristen Clermont ◽  
Yaxin Wang ◽  
Siming Liu ◽  
Zhenzhen Yang ◽  
Claude dePamphilis ◽  
...  
Keyword(s):  
Amino Acid ◽  
Vascular Tissue ◽  
Acid Biosynthesis ◽  
Parasitic Weeds ◽  
The Family ◽  
Metabolite Profiles ◽  
Before And After ◽  
Comparative Metabolomics ◽  
15N Labeling ◽  
Aspartate Family

Parasitic weeds of the family Orobanchaceae attach to the roots of host plants via haustoria capable of drawing nutrients from host vascular tissue. The connection of the haustorium to the host marks a shift in parasite metabolism from autotrophy to at least partial heterotrophy, depending on the level of parasite dependence. Species within the family Orobanchaceae span the spectrum of host nutrient dependency, yet the diversity of parasitic plant metabolism remains poorly understood, particularly during the key metabolic shift surrounding haustorial attachment. Comparative profiling of major metabolites in the obligate holoparasite Phelipanche aegyptiaca and the facultative hemiparasite Triphysaria versicolor before and after attachment to the hosts revealed several metabolic shifts implicating remodeling of energy and amino acid metabolism. After attachment, both parasites showed metabolite profiles that were different from their respective hosts. In P. aegyptiaca, prominent changes in metabolite profiles were also associated with transitioning between different tissue types before and after attachment, with aspartate levels increasing significantly after the attachment. Based on the results from 15N labeling experiments, asparagine and/or aspartate-rich proteins were enriched in host-derived nitrogen in T. versicolor. These results point to the importance of aspartate and/or asparagine in the early stages of attachment in these plant parasites and provide a rationale for targeting aspartate-family amino acid biosynthesis for disrupting the growth of parasitic weeds.

scholarly journals MNGI-01. A PHASE 0 TRIAL OF RIBOCICLIB IN AGGRESSIVE MENINGIOMA PATIENTS INCORPORATING A TUMOR PHARMACODYNAMIC- AND PHARMACOKINETIC-GUIDED EXPANSION COHORT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi139-vi139
Author(s):  
An-Chi Tien ◽  
Jing Li ◽  
Xun Bao ◽  
Alanna DeRogatis ◽  
Yoko Fujita ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Tumor Tissue ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Who Grade ◽  
Drug Concentrations ◽  
Grade Ii ◽  
Expansion Cohort ◽  
Pharmacologically Active

Abstract BACKGROUND New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients. METHODS Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04µM) and >20% decrease in pRB levels, respectively, were enrolled into an expansion cohort for preliminary assessment of progression-free survival. RESULTS The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At 14 months, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria. CONCLUSION Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

scholarly journals Mitochondrial DNA Content Varies with Pathological Characteristics of Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ren-Kui Bai ◽  
Julia Chang ◽  
Kun-Tu Yeh ◽  
Mary Ann Lou ◽  
Jyh-Feng Lu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Tumor Size ◽  
Small Sample Size ◽  
Small Sample ◽  
Coding Region ◽  
Normal Tissues ◽  
Pathological Characteristics ◽  
Loop Region ◽  
Tumor Tissues ◽  
Grade Ii

Changes in mitochondrial DNA (mtDNA) content in cancers have been reported with controversial results, probably due to small sample size and variable pathological conditions. In this study, mtDNA content in 302 breast tumor/surrounding normal tissue pairs were evaluated and correlated with the clinico-pathological characteristics of tumors. Overall, mtDNA content in tumor tissues is significantly lower than that in the surrounding normal tissues,P<0.00001. MtDNA content in tumor tissues decreased with increasing tumor size. However, when the tumor is very large (>50 cm3), mtDNA content started to increase. Similarly, mtDNA content decreased from grades 0 and I to grade II tumors, but increased from grade II to grade III tumors. Tumors with somatic mtDNA alterations in coding region have significantly higher mtDNA content than tumors without somatic mtDNA alterations (P<0.001). Tumors with somatic mtDNA alterations in the D-Loop region have significantly lower mtDNA content (P<0.001). Patients with both low and high mtDNA content in tumor tissue have significantly higher hazard of death than patients with median levels of mtDNA content. mtDNA content in tumor tissues change with tumor size, grade, and ER/PR status; significant deviation from the median level of mtDNA content is associated with poor survival.

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