| Literature DB >> 33772001 |
Emily Golden1,2, Rabab Rashwan1,2,3, Eleanor A Woodward1,2, Agustin Sgro1,2,4, Edina Wang1,2, Anabel Sorolla1,2, Charlene Waryah1,2, Wan Jun Tie1,2, Elisabet Cuyàs1,5,6, Magdalena Ratajska7,8,9, Iwona Kardaś7,10, Piotr Kozlowski11, Elizabeth K M Johnstone2,12,13, Heng B See2,12,13, Ciara Duffy1,2,4, Jeremy Parry14, Kim A Lagerborg15, Piotr Czapiewski16,17, Javier A Menendez5,6, Adam Gorczyński16, Bartosz Wasag7,10, Kevin D G Pfleger2,12,13,18, Christina Curtis19, Bum-Kyu Lee20, Jonghwan Kim21, Joseph Cursons22, Nathan J Pavlos8,23, Wojciech Biernat16, Mohit Jain15, Andrew J Woo2,24, Andrew Redfern25, Pilar Blancafort26,27,28,29.
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.Entities:
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Year: 2021 PMID： 33772001 DOI： 10.1038/s41467-021-22101-7
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919