The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer
| Autor: | Kevin D. G. Pfleger, Wan Jun Tie, Joseph Cursons, Bum-Kyu Lee, Piotr Kozlowski, Edina Wang, Rabab Rashwan, Ciara Duffy, Mohit Jain, Magdalena Ratajska, Wojciech Biernat, Pilar Blancafort, Piotr Czapiewski, Anabel Sorolla, Agustin Sgro, Andrew J. Woo, Christina Curtis, Jeremy Parry, Kim A. Lagerborg, Charlene Babra Waryah, Elizabeth K. M. Johnstone, Jonghwan Kim, Bartosz Wasag, Eleanor A. Woodward, Javier A. Menendez, Nathan J. Pavlos, Emily Golden, Andrew Redfern, Iwona Kardaś, Heng B. See, Elisabet Cuyàs, Adam Gorczyński |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Science General Physics and Astronomy Estrogen receptor Antineoplastic Agents Breast Neoplasms Cell Cycle Proteins Nerve Tissue Proteins Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Breast cancer medicine Humans Everolimus Protein kinase B PI3K/AKT/mTOR pathway Regulation of gene expression Multidisciplinary Oncogene TOR Serine-Threonine Kinases ATF4 GTPase-Activating Proteins Imidazoles Cancer General Chemistry Oncogenes medicine.disease Cancer metabolism Gene Expression Regulation Neoplastic 030104 developmental biology Receptors Estrogen Adipogenesis 030220 oncology & carcinogenesis Cancer research Quinolines Female Proto-Oncogene Proteins c-akt Protein Binding Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-22 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Adipogenesis associated Mth938 Domain Containing gene (AAMDC) is frequently amplified in the IntClus2 subgroup of ER + breast cancer. Here, the authors show that AAMDC drives tumourigenesis through activating PI3K-AKT-mTOR pathway for metabolic reprogramming. |
| Databáze: | OpenAIRE |
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