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Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Author

Listed:
  • Richard Possemato

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Kevin M. Marks

    (Agios Pharmaceuticals, 38 Sidney Street)

  • Yoav D. Shaul

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Michael E. Pacold

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Dohoon Kim

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Kıvanç Birsoy

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Shalini Sethumadhavan

    (Agios Pharmaceuticals, 38 Sidney Street)

  • Hin-Koon Woo

    (Agios Pharmaceuticals, 38 Sidney Street)

  • Hyun G. Jang

    (Agios Pharmaceuticals, 38 Sidney Street)

  • Abhishek K. Jha

    (Agios Pharmaceuticals, 38 Sidney Street)

  • Walter W. Chen

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Francesca G. Barrett

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center)

  • Nicolas Stransky

    (Broad Institute of Harvard and MIT, Seven Cambridge Center)

  • Zhi-Yang Tsun

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Glenn S. Cowley

    (Broad Institute of Harvard and MIT, Seven Cambridge Center)

  • Jordi Barretina

    (Broad Institute of Harvard and MIT, Seven Cambridge Center
    Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Nada Y. Kalaany

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Peggy P. Hsu

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Kathleen Ottina

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Albert M. Chan

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

  • Bingbing Yuan

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center)

  • Levi A. Garraway

    (Broad Institute of Harvard and MIT, Seven Cambridge Center
    Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • David E. Root

    (Broad Institute of Harvard and MIT, Seven Cambridge Center)

  • Mari Mino-Kenudson

    (Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • Elena F. Brachtel

    (Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • Edward M. Driggers

    (Agios Pharmaceuticals, 38 Sidney Street)

  • David M. Sabatini

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Massachusetts Institute of Technology
    Broad Institute of Harvard and MIT, Seven Cambridge Center
    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue)

Abstract

Serine biosynthesis target in breast cancer An in vivo RNAi screen of metabolic enzymes and transporters is used to identify, among other genes, phosphoglycerate dehydrogenase (PHGDH) as a gene required for breast tumour growth. PHGDH resides in a region of chromosome 1p that is often amplified in breast cancers, leading to PHGDH overexpression. Elevated levels of PHGDH cause increased metabolic flux through the serine synthesis pathway, which in turn contributes significantly to the flux of glutamine to α-ketoglutarate through the tricarboxylic acid cycle. These observations suggest that targeting PHGDH or the serine biosynthesis pathway in general might be of therapeutic value in the subset of breast cancers with high PHGDH expression.

Suggested Citation

  • Richard Possemato & Kevin M. Marks & Yoav D. Shaul & Michael E. Pacold & Dohoon Kim & Kıvanç Birsoy & Shalini Sethumadhavan & Hin-Koon Woo & Hyun G. Jang & Abhishek K. Jha & Walter W. Chen & Francesca, 2011. "Functional genomics reveal that the serine synthesis pathway is essential in breast cancer," Nature, Nature, vol. 476(7360), pages 346-350, August.
    • Handle: RePEc:nat:nature:v:476:y:2011:i:7360:d:10.1038_nature10350
    DOI: 10.1038/nature10350
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    Cited by:

    1. Gabrielle Manteaux & Alix Amsel & Blanche Riquier-Morcant & Jaime Prieto Romero & Laurie Gayte & Benjamin Fourneaux & Marion Larroque & Nadège Gruel & Chloé Quignot & Gaelle Perot & Solenn Jacq & Madi, 2024. "A metabolic crosstalk between liposarcoma and muscle sustains tumor growth," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Nicole Kiweler & Catherine Delbrouck & Vitaly I. Pozdeev & Laura Neises & Leticia Soriano-Baguet & Kim Eiden & Feng Xian & Mohaned Benzarti & Lara Haase & Eric Koncina & Maryse Schmoetten & Christian , 2022. "Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Seong Eun Lee & Seongyeol Park & Shinae Yi & Na Rae Choi & Mi Ae Lim & Jae Won Chang & Ho-Ryun Won & Je Ryong Kim & Hye Mi Ko & Eun-Jae Chung & Young Joo Park & Sun Wook Cho & Hyeong Won Yu & June You, 2024. "Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Camilla Tombari & Alessandro Zannini & Rebecca Bertolio & Silvia Pedretti & Matteo Audano & Luca Triboli & Valeria Cancila & Davide Vacca & Manuel Caputo & Sara Donzelli & Ilenia Segatto & Simone Vodr, 2023. "Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Eirini Lionaki & Ilias Gkikas & Ioanna Daskalaki & Maria-Konstantina Ioannidi & Maria I. Klapa & Nektarios Tavernarakis, 2022. "Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Marc Hennequart & Christiaan F. Labuschagne & Mylène Tajan & Steven E. Pilley & Eric C. Cheung & Nathalie M. Legrave & Paul C. Driscoll & Karen H. Vousden, 2021. "The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    9. Emmanuel Benichou & Bolaji Seffou & Selin Topçu & Ophélie Renoult & Véronique Lenoir & Julien Planchais & Caroline Bonner & Catherine Postic & Carina Prip-Buus & Claire Pecqueur & Sandra Guilmeau & Ma, 2024. "The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism," Nature Communications, Nature, vol. 15(1), pages 1-29, December.

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