Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences

Stewart, Delisha A.; Winnike, Jason H.; McRitchie, Susan; Clark, Robert; Pathmasiri, Wimal; Sumner, Susan

doi:10.1021/acs.jproteome.6b00430

Cited by 44 publications

(41 citation statements)

References 113 publications

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“…Our KEGG pathway computational analysis revealed that miR-95 is involved in different cellular processes, including lysine degradation. This is in agreement with a previous study that demonstrated that lysine is a metabolite that distinguishes TNBC cells from hormone-positive breast cancer cells (72). Given that the amino acid metabolism is a major source of energy and carbon for tumor cell growth and survival (73), the dysregulation of the lysine degradation pathway may result from changes in the energy metabolism of tumor cells.…”

Section: Discussionsupporting

confidence: 92%

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

et al. 2018

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Triple-negative breast cancers (TNBCs) account for ∼25% of all invasive carcinomas and represent a large subset of aggressive, high-grade tumors. Despite current research focused on understanding the genetic landscape of TNBCs, reliable prognostic and predictive biomarkers remain limited. Although dysregulated microRNAs (miRNAs) have emerged as key players in many cancer types, the role of miRNAs in TNBC disease progression is unclear. We performed miRNA profiling of 51 TNBCs by next-generation sequencing to reveal differentially expressed miRNAs. A total of 228 miRNAs were identified. Three miRNAs (miR-224-5p, miR-375, and miR-205-5p) separated the tumors based on basal status. Six miRNAs (high let-7d-3p, miR-203b-5p, and miR-324-5p; low miR-30a-3p, miR-30a-5p, and miR-199a-5p) were significantly associated with decreased overall survival (OS) and 5 miRNAs (high let-7d-3p; low miR-30a-3p, miR-30a-5p, miR-30c-5p, and miR-128-3p) with decreased relapse-free survival (RFS). On multivariate analysis, high expression of let-7d-3p and low expression of miR-30a were independent predictors of decreased OS and RFS. High expression of miR-95-3p was significantly associated with decreased OS and RFS in patients treated with anthracycline-based chemotherapy. Five miRNAs (let-7d-3p, miR-30a-3p, miR-30c-5p, miR-128-3p, and miR-95-3p) were validated by quantitative RT-PCR. Our findings unveil novel prognostic and predictive miRNA targets for TNBC, including a miRNA signature that predicts patient response to anthracycline-based chemotherapy. This may improve clinical management and/or lead to the development of novel therapies.-Turashvili, G., Lightbody, E. D., Tyryshkin, K., SenGupta, S. K., Elliott, B. E., Madarnas, Y., Ghaffari, A., Day, A., Nicol, C. J. B. Novel prognostic and predictive microRNA targets for triple-negative breast cancer.

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Section: Discussionsupporting

confidence: 92%

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

et al. 2018

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“…In a previous study [ 26 ], we compared the metabolic and inflammatory responses of these hormone receptor-positive (Luminal A) and TNBC cell lines following treatment with the widely used chemotherapeutic paclitaxel (Taxol®). There, we showed differences between both the cells classified by the same subtype (BT474 versus MCF-7 and MDA-MB-231 versus MDA-MB-468) and between the two subtype cell models (Luminal A versus TNBC) [ 26 ]. Based on our findings, we felt further investigation of the metabolic differences was warranted.…”

Section: Introductionmentioning

confidence: 99%

Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines

Winnike

Stewart

Pathmasiri

et al. 2018

International Journal of Breast Cancer

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Purpose To conduct an exploratory study to identify mechanisms that differentiate Luminal A (BT474 and MCF-7) and triple-negative (MDA-MB-231 and MDA-MB-468) breast cancer (BCa) cell lines to potentially provide novel therapeutic targets based on differences in energy utilization. Methods Cells were cultured in media containing either [U-13C]-glucose or [U-13C]-glutamine for 48 hours. Conditioned media and cellular extracts were analyzed by 1H and 13C NMR spectroscopy. Results MCF-7 cells consumed the most glucose, producing the most lactate, demonstrating the greatest Warburg effect-associated energy utilization. BT474 cells had the highest tricarboxylic acid cycle (TCA) activity. The majority of energy utilization patterns in MCF-7 cells were more similar to MDA-MB-468 cells, while the patterns for BT474 cells were more similar to MDA-MB-231 cells. Compared to the Luminal A cell lines, TNBC cell lines consumed more glutamine and less glucose. BT474 and MDA-MB-468 cells produced high amounts of 13C-glycine from media [U-13C]-glucose which was integrated into glutathione, indicating de novo synthesis. Conclusions Stable isotopic resolved metabolomics using 13C substrates provided mechanistic information about energy utilization that was difficult to interpret using 1H data alone. Overall, cell lines that have different hormone receptor status have different energy utilization requirements, even if they are classified by the same clinical BCa subtype; and these differences offer clues about optimizing treatment strategies.

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“…Previous studies demonstrated that 1 and 3nM PTX had an impact on morphology and viability of cancer cells. 10,19 Therefore, we investigated whether PTX at concentration (1-3 nM) had similar effects in mtp53 HPSCC. The results showed that PTX at a concentration (1-3 nM) did not inhibit cell growth ( Figure 1B).…”

Section: Low Concentration Ptx Did Not Affect Cell Viability Of Mtp53mentioning

confidence: 99%

<p>Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma</p>

Ye¹,

Jiang²,

Dong³

et al. 2019

CMAR

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Introduction: RSL3-induced ferroptosis is a cell death pathway dependent upon intracellular iron and is characterized by accumulation of lipid hydroperoxides. Glutaminolysis, a glutamine-fueled intracellular metabolic pathway, is an essential pathway of ferroptosis in cancer cells. Recent findings showed low-concentration paclitaxel (PTX) could inhibit cell death by upregulating p53 expression; downregulating glutaminolysis-related genes. Methods: The therapeutic effect of RSL3 plus low-concentration PTX combination therapy was investigated in HPSCC cells harboring mutant p53 (mtp53). Relative cell viability, ferroptosis-specific lipid peroxidation and relevant protein expression were evaluated. Results: We demonstrated that neither PTX nor RSL3 in low concentration caused significant cell death; however, the combination therapy is shown to induce ferroptosis and significant cell death in mtp53 HPSCC. We discovered that low-concentration PTX enhanced the RSL3-induced ferroptosis by upregulating mtp53 expression. Furthermore, mtp53mediated transcriptional regulation of SLC7A11 could be the key determinant. Discussion: Although gain-of-function of p53 variants remains to be characterized, our findings provide new insight into the synergistical cell death by regulating ferroptosis and p53.

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Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences

Cited by 44 publications

References 113 publications

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

Novel prognostic and predictive microRNA targets for triple‐negative breast cancer

Stable Isotope-Resolved Metabolomic Differences between Hormone-Responsive and Triple-Negative Breast Cancer Cell Lines

<p>Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma</p>

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