The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer
Emily Golden, Rana Rashwan, Eleanor Woodward, Agustin Sgro, Edina Wang, Anabel Sorolla, Charlene Waryah, Wan Jun Tie, Elisabet Cuyàs, Magdalena Ratajska, Iwona Kardaś, Piotr Kozłowski, Elizabeth K. M. Johnstone, Heng B. See, Ciara Duffy, Jeremy Parry, Kim A. Lagerborg, Piotr Czapiewski, Javier A. Menéndez, Adam Gorczyński, Bartosz Wasąg, 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
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.