Evidence map›Paper›PMID 26229077›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2015

Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype.

Haiquan Lu, Debangshu Samanta, Lisha Xiang, Huimin Zhang, Hongxia Hu, Ivan Chen, John W Bullen, Gregg L Semenza

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 159 papers.

0numbers the graph read from it
0cells of the map it votes in
159citing papers in PubMed
7.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

159 citing papers in PubMed, 265 citations in OpenAlex.

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  15. Resistance to neoadjuvant chemotherapy in breast cancers: a metabolic perspective.Journal of experimental & clinical cancer research : CR · 2025
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99 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 1 country.

Haiquan LuJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Debangshu SamantaJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Lisha XiangJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Huimin ZhangJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Hongxia HuJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Ivan ChenJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
John W BullenJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Gregg L SemenzaJohns Hopkins Institute for Cell Engineering and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu.
Johns Hopkins Medicine · USJohns Hopkins University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.

Indexed as

AnimalsAntineoplastic AgentsCell Line, TumorChelating AgentsCopperExtracellular Signal-Regulated MAP KinasesFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGlutathioneHumansHypoxia-Inducible Factor 1, alpha SubunitMAP Kinase Kinase KinasesMAP Kinase Signaling SystemMiceMice, SCIDAntineoplastic AgentsChelating AgentsCopperExtracellular Signal-Regulated MAP KinasesGlutathioneHIF1A protein, humanHypoxia-Inducible Factor 1, alpha SubunitMAP Kinase Kinase KinasesOligonucleotidesPaclitaxelRNA, Messengerchemotherapy resistancehypoxia-inducible factorpaclitaxelpluripotency factorstumor-initiating cells

Identifiers

PMID26229077
PMCPMC4547233
OpenAlexW1868543250

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.