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, Pilar Blancafort
Nature communications 2021 Mar 26Adipogenesis 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.
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, 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, Pilar Blancafort. The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer. Nature communications. 2021 Mar 26;12(1):1920
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PMID: 33772001
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