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The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.
Golden, Emily; Rashwan, Rabab; Woodward, Eleanor A; Sgro, Agustin; Wang, Edina; Sorolla, Anabel; Waryah, Charlene; Tie, Wan Jun; Cuyàs, Elisabet; Ratajska, Magdalena; Kardas, Iwona; Kozlowski, Piotr; Johnstone, Elizabeth K M; See, Heng B; Duffy, Ciara; Parry, Jeremy; Lagerborg, Kim A; Czapiewski, Piotr; Menendez, Javier A; Gorczynski, Adam; Wasag, Bartosz; Pfleger, Kevin D G; Curtis, Christina; Lee, Bum-Kyu; Kim, Jonghwan; Cursons, Joseph; Pavlos, Nathan J; Biernat, Wojciech; Jain, Mohit; Woo, Andrew J; Redfern, Andrew; Blancafort, Pilar.
Afiliação
  • Golden E; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Rashwan R; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Woodward EA; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Sgro A; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Wang E; Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt.
  • Sorolla A; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Waryah C; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Tie WJ; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Cuyàs E; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Ratajska M; School of Human Sciences, The University of Western Australia, Perth, WA, Australia.
  • Kardas I; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Kozlowski P; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Johnstone EKM; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • See HB; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Duffy C; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Parry J; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Lagerborg KA; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Czapiewski P; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Menendez JA; Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Gorczynski A; Girona Biomedical Research Institute, Girona, Catalonia, Spain.
  • Wasag B; ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.
  • Pfleger KDG; Department of Biology and Medical Genetics, Medical University of Gdansk, Gdansk, Poland.
  • Curtis C; The Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
  • Lee BK; Department of Pathology, Otago University, Dunedin, New Zealand.
  • Kim J; Department of Biology and Medical Genetics, Medical University of Gdansk, Gdansk, Poland.
  • Cursons J; Laboratory of Clinical Genetics, University Clinical Centre, Gdansk, Poland.
  • Pavlos NJ; Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
  • Biernat W; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Jain M; Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
  • Woo AJ; Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne and Perth, Australia.
  • Redfern A; Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
  • Blancafort P; Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
Nat Commun ; 12(1): 1920, 2021 03 26.
Article em En | MEDLINE | ID: mdl-33772001
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas de Ciclo Celular / Fosfatidilinositol 3-Quinases / Proteínas Proto-Oncogênicas c-akt / Serina-Treonina Quinases TOR Limite: Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas de Ciclo Celular / Fosfatidilinositol 3-Quinases / Proteínas Proto-Oncogênicas c-akt / Serina-Treonina Quinases TOR Limite: Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article