TY - JOUR
T1 - The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer
AU - Golden, Emily
AU - Rashwan, Rabab
AU - Woodward, Eleanor A.
AU - Sgro, Agustin
AU - Wang, Edina
AU - Sorolla, Anabel
AU - Waryah, Charlene
AU - Tie, Wan Jun
AU - Cuyàs, Elisabet
AU - Kardaś, Iwona
AU - Kozlowski, Piotr
AU - Johnstone, Elizabeth K.M.
AU - See, Heng B.
AU - Duffy, Ciara
AU - Parry, Jeremy
AU - Lagerborg, Kim A.
AU - Czapiewski, Piotr
AU - Menendez, Javier A.
AU - Gorczyński, Adam
AU - Wasag, Bartosz
AU - Pfleger, Kevin D.G.
AU - Curtis, Christina
AU - Lee, Bum Kyu
AU - Kim, Jonghwan
AU - Cursons, Joseph
AU - Pavlos, Nathan J.
AU - Biernat, Wojciech
AU - Jain, Mohit
AU - Woo, Andrew J.
AU - Redfern, Andrew
AU - Blancafort, Pilar
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85103386785&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22101-7
DO - 10.1038/s41467-021-22101-7
M3 - Article
C2 - 33772001
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1920
ER -