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The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

Author

Listed:
  • Emily Golden

    (The University of Western Australia
    The University of Western Australia)

  • Rabab Rashwan

    (The University of Western Australia
    The University of Western Australia
    Minia University)

  • Eleanor A. Woodward

    (The University of Western Australia
    The University of Western Australia)

  • Agustin Sgro

    (The University of Western Australia
    The University of Western Australia
    The University of Western Australia)

  • Edina Wang

    (The University of Western Australia
    The University of Western Australia)

  • Anabel Sorolla

    (The University of Western Australia
    The University of Western Australia)

  • Charlene Waryah

    (The University of Western Australia
    The University of Western Australia)

  • Wan Jun Tie

    (The University of Western Australia
    The University of Western Australia)

  • Elisabet Cuyàs

    (The University of Western Australia
    Girona Biomedical Research Institute
    Catalan Institute of Oncology)

  • Magdalena Ratajska

    (Medical University of Gdansk
    The University of Western Australia
    Otago University)

  • Iwona Kardaś

    (Medical University of Gdansk
    University Clinical Centre)

  • Piotr Kozlowski

    (Polish Academy of Sciences)

  • Elizabeth K. M. Johnstone

    (The University of Western Australia
    Harry Perkins Institute of Medical Research
    Australian Research Council Centre for Personalised Therapeutics Technologies)

  • Heng B. See

    (The University of Western Australia
    Harry Perkins Institute of Medical Research
    Australian Research Council Centre for Personalised Therapeutics Technologies)

  • Ciara Duffy

    (The University of Western Australia
    The University of Western Australia
    The University of Western Australia)

  • Jeremy Parry

    (Fiona Stanley Hospital Network)

  • Kim A. Lagerborg

    (University of California)

  • Piotr Czapiewski

    (Medical University of Gdansk
    Institute of Pathology, Dessau Medical Centre)

  • Javier A. Menendez

    (Girona Biomedical Research Institute
    Catalan Institute of Oncology)

  • Adam Gorczyński

    (Medical University of Gdansk)

  • Bartosz Wasag

    (Medical University of Gdansk
    University Clinical Centre)

  • Kevin D. G. Pfleger

    (The University of Western Australia
    Harry Perkins Institute of Medical Research
    Australian Research Council Centre for Personalised Therapeutics Technologies
    Dimerix Limited)

  • Christina Curtis

    (Stanford University School of Medicine (Departments of Medicine & Genetics) and Stanford Cancer Institute)

  • Bum-Kyu Lee

    (University at Albany-State University of New York)

  • Jonghwan Kim

    (The University of Texas at Austin)

  • Joseph Cursons

    (Monash University)

  • Nathan J. Pavlos

    (The University of Western Australia
    The University of Western Australia)

  • Wojciech Biernat

    (Medical University of Gdansk)

  • Mohit Jain

    (University of California)

  • Andrew J. Woo

    (The University of Western Australia
    Edith Cowan University)

  • Andrew Redfern

    (University of Western Australia)

  • Pilar Blancafort

    (The University of Western Australia
    The University of Western Australia
    The University of Western Australia
    The University of Texas Health Science Center at San Antonio)

Abstract

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.

Suggested Citation

  • Emily Golden & Rabab Rashwan & Eleanor A. Woodward & Agustin Sgro & Edina Wang & Anabel Sorolla & Charlene Waryah & Wan Jun Tie & Elisabet Cuyàs & Magdalena Ratajska & Iwona Kardaś & Piotr Kozlowski &, 2021. "The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22101-7
    DOI: 10.1038/s41467-021-22101-7
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