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

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

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

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Research Themes

Health

Priority Areas

Prevention, detection and management of cancer and other chronic diseases

Included in

Diseases Commons

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