Document Type
Journal Article
Publication Title
Nature Communications
Volume
12
Issue
1
Publisher
Nature
School
School of Medical and Health Sciences
RAS ID
35503
Funders
Funding information : https://doi.org/10.1038/s41467-021-22101-7 National Health and Medical Research Council Australian Resarch Council Fellowship
Grant Number
ARC Number : FT130101767NHMRC Number : APP1069308, APP1147528, APP1130212
Grant Link
http://purl.org/au-research/grants/arc/FT130101767 http://purl.org/au-research/grants/nhmrc/1069308 http://purl.org/au-research/grants/nhmrc/1147528 http://purl.org/au-research/grants/nhmrc/1130212
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.
DOI
10.1038/s41467-021-22101-7
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Golden, E., Rashwan, R., Woodward, E. A., Sgro, A., Wang, E., Sorolla, A., ... Blancafort, P. (2021). The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer. Nature Communications, 12, article 1920. https://doi.org/10.1038/s41467-021-22101-7