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

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, Elizabeth K. M. Johnstone, Heng B. See, Ciara Duffy, Jeremy Parry, Kim A. Lagerborg, Piotr Czapiewski, Javier A. Menendez, Adam Gorczyński, Bartosz Wasag, Kevin D. G. Pfleger, Christina Curtis, Bum-Kyu Lee, Jonghwan Kim, Joseph Cursons, Nathan J. Pavlos, Wojciech Biernat, Mohit Jain, Andrew J. Woo, Andrew Redfern and Pilar Blancafort ()
Additional contact information
Emily Golden: The University of Western Australia
Rabab Rashwan: The University of Western Australia
Eleanor A. Woodward: The University of Western Australia
Agustin Sgro: The University of Western Australia
Edina Wang: The University of Western Australia
Anabel Sorolla: The University of Western Australia
Charlene Waryah: The University of Western Australia
Wan Jun Tie: The University of Western Australia
Elisabet Cuyàs: The University of Western Australia
Magdalena Ratajska: Medical University of Gdansk
Iwona Kardaś: Medical University of Gdansk
Piotr Kozlowski: Polish Academy of Sciences
Elizabeth K. M. Johnstone: The University of Western Australia
Heng B. See: The University of Western Australia
Ciara Duffy: The University of Western Australia
Jeremy Parry: Fiona Stanley Hospital Network
Kim A. Lagerborg: University of California
Piotr Czapiewski: Medical University of Gdansk
Javier A. Menendez: Girona Biomedical Research Institute
Adam Gorczyński: Medical University of Gdansk
Bartosz Wasag: Medical University of Gdansk
Kevin D. G. Pfleger: The University of Western Australia
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
Wojciech Biernat: Medical University of Gdansk
Mohit Jain: University of California
Andrew J. Woo: The University of Western Australia
Andrew Redfern: University of Western Australia
Pilar Blancafort: The University of Western Australia

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22101-7

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