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Cited by 248Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 135 of the 135 references it cites were found in a registry or an index.

Metabolic reprogramming in triple-negative breast cancer

Open access
Wang, Zhanyu, Jiang, Qianjin, Dong, Chenfang·2020·Cancer Biology and Medicine
DOI 10.20892/j.issn.2095-3941.2019.0210PMC PMC7142847
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Abstract

Since triple-negative breast cancer (TNBC) was first defined over a decade ago, increasing studies have focused on its genetic and molecular characteristics. Patients diagnosed with TNBC, compared to those diagnosed with other breast cancer subtypes, have relatively poor outcomes due to high tumor aggressiveness and lack of targeted treatment. Metabolic reprogramming, an emerging hallmark of cancer, is hijacked by TNBC to fulfill bioenergetic and biosynthetic demands; maintain the redox balance; and further promote oncogenic signaling, cell proliferation, and metastasis. Understanding the mechanisms of metabolic remodeling may guide the design of metabolic strategies for the effective intervention of TNBC. Here, we review the metabolic reprogramming of glycolysis, oxidative phosphorylation, amino acid metabolism, lipid metabolism, and other branched pathways in TNBC and explore opportunities for new biomarkers, imaging modalities, and metabolically targeted therapies.

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Crossref · 10.20892/j.issn.2095-3941.2019.0210

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Figure 1 Metabolic reprogramming in triple-negative breast cancer (TNBC). TNBC upregulates several key glycolytic enzymes and transporters such as GLUT, HK, LDH, and MCT, therefore displaying high rate of glycolysis and glycolytic branched pathways, including serine synthesis and pentose phosphate pathway (PPP) for NADPH generation, and hexosamine biosynthetic pathway (HBP) for protein glycosylation. Other pathways such as fatty acid oxidation (FAO), glutaminolysis and cystine uptake are also induced in TNBC to meet its bioenergetic or biosynthetic demands, and mitigate reactive oxygen species (ROS) that is generated from oxidative phosphorylation (OXPHOS). Enzymes that are upregulated in TNBC are shown as light-yellow ovals, and enzymes downregulated in TNBC are shown as gray ovals.
Figure 1 Metabolic reprogramming in triple-negative breast cancer (TNBC). TNBC upregulates several key glycolytic enzymes and transporters such as GLUT, HK, LDH, and MCT, therefore displaying high rate of glycolysis and glycolytic branched pathways, including serine synthesis and pentose phosphate pathway (PPP) for NADPH generation, and hexosamine biosynthetic pathway (HBP) for protein glycosylation. Other pathways such as fatty acid oxidation (FAO), glutaminolysis and cystine uptake are also induced in TNBC to meet its bioenergetic or biosynthetic demands, and mitigate reactive oxygen species (ROS) that is generated from oxidative phosphorylation (OXPHOS). Enzymes that are upregulated in TNBC are shown as light-yellow ovals, and enzymes downregulated in TNBC are shown as gray ovals.CC BY · PubMed Central
Figure 2 Switchable metabolic dependence on glycolysis and oxidative phosphorylation (OXPHOS) regulated by HIF-1α and AMPK. Under normoxic condition, HIF-1α is hydroxylated and subsequently degraded by PHD2 in an α-KG- and cysteine-dependent manner. In TNBC, decreased levels of α-KG and cysteine due to altered activity of transketolase (TKT) and xCT cystine/glutamate antiporter, respectively, contribute to normoxic activation of HIF-1α signaling, which triggers aerobic glycolysis with the upregulation of glycolysis-related enzymes and transporters. Although TNBC cells rely on glycolysis for rapid proliferation, OXPHOS which generate ATP more efficiently is also required, especially under bioenergetic stress. Activated AMPK and Myc pathways induce mitochondrial biogenesis and enzymes involved in glutaminolysis and fatty acid oxidation (FAO) to facilitate OXPHOS, thus endowing TNBC with metabolic plasticity to switch between glycolysis and OXPHOS. In addition, AMPK signaling also promotes epithelial-mesenchymal transition (EMT) through regulating lipid metabolism and increases the secretion of cytokines to recruit immunosuppressive myeloid-derived suppressor cells (MDSCs). Many drugs have been developed to target these key processes in the metabolic reprogramming of TNBC.
Figure 2 Switchable metabolic dependence on glycolysis and oxidative phosphorylation (OXPHOS) regulated by HIF-1α and AMPK. Under normoxic condition, HIF-1α is hydroxylated and subsequently degraded by PHD2 in an α-KG- and cysteine-dependent manner. In TNBC, decreased levels of α-KG and cysteine due to altered activity of transketolase (TKT) and xCT cystine/glutamate antiporter, respectively, contribute to normoxic activation of HIF-1α signaling, which triggers aerobic glycolysis with the upregulation of glycolysis-related enzymes and transporters. Although TNBC cells rely on glycolysis for rapid proliferation, OXPHOS which generate ATP more efficiently is also required, especially under bioenergetic stress. Activated AMPK and Myc pathways induce mitochondrial biogenesis and enzymes involved in glutaminolysis and fatty acid oxidation (FAO) to facilitate OXPHOS, thus endowing TNBC with metabolic plasticity to switch between glycolysis and OXPHOS. In addition, AMPK signaling also promotes epithelial-mesenchymal transition (EMT) through regulating lipid metabolism and increases the secretion of cytokines to recruit immunosuppressive myeloid-derived suppressor cells (MDSCs). Many drugs have been developed to target these key processes in the metabolic reprogramming of TNBC.CC BY · PubMed Central

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Metadata

Authors
Wang, Z., Jiang, Q., & Dong, C.
Affiliations
  • Second Affiliated Hospital of Zhejiang University (CN)
  • Zhejiang University (CN)
Corresponding author
Dong, Chenfang
ORCID
Venue
Cancer Biology and Medicine
Publisher
China Anti-cancer Association
Published
2020
Volume
17
Issue
1
Pages
44-59
ISSN
2095-3941 (ISSN-L)
DOI
10.20892/j.issn.2095-3941.2019.0210
PMC
PMC7142847
OpenAlex
W3020548503
Cited by
248
References
135
Citations by year
2026: 61 · 2025: 63 · 2024: 46 · 2023: 31 · 2022: 20 · 2021: 18 · 2020: 8
FWCI
6.58
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cancer Biology and Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
triple-negative breast cancer, metabolic reprogramming, glycolysis, oxidative phosphorylation, amino acid metabolism, lipid metabolism, redox homeostasis, oncogenic signaling, metastasis, metabolic biomarkers, metabolic imaging
MeSH terms
Warburg Effect, Oncologic, Amino Acids, Antineoplastic Agents, Female, Humans, Oxidative Phosphorylation, Biomarkers, Tumor, Lipid Metabolism, Molecular Targeted Therapy, Triple Negative Breast Neoplasms

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