MEN1 silencing triggers the dysregulation of mTORC1 and MYC pathways in ER+ breast cancer cells - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue Endocrine-Related Cancer Année : 2022

MEN1 silencing triggers the dysregulation of mTORC1 and MYC pathways in ER+ breast cancer cells

Résumé

Menin, encoded by the MEN1 gene, has been identified as a critical factor regulating ESR1 transcription, playing an oncogenic role in ER+ breast cancer (BC) cells. Here, we further dissected the consequences of menin inactivation in ER+ BC cells by focusing on factors within two major pathways involved in BC, mTOR and MYC. MEN1 silencing in MCF7 and T-47D resulted in an increase in phosphor-p70S6K1, phosphor-p85S6K1 and phosphor-4EBP1 expression. The use of an AKT inhibitor inhibited the activation of S6K1 and S6RP triggered by MEN1 knockdown (KD). Moreover, MEN1 silencing in ER+ BC cells led to increased formation of the eIF4E and 4G complex. Clinical studies showed that patients with menin-low breast cancer receiving tamoxifen plus everolimus displayed a trend toward better overall survival. Importantly, MEN1 KD in MCF7 and T-47D cells led to reduced MYC expression. ChIP analysis demonstrated that menin bound not only to the MYC promoter but also to its 5’ enhancer. Furthermore, E2-treated MEN1 KD MCF7 cells displayed a decrease in MYC activation, suggesting its role in estrogen-mediated MYC transcription. Finally, expression data mining in tumors revealed a correlation between the expression of MEN1 mRNA and that of several mTORC1 components and targets and a significant inverse correlation between MEN1 and two MYC inhibitory factors, MYCBP2 and MYCT1 , in ER+ BC. The current work thus highlights altered mTORC1 and MYC pathways after menin inactivation in ER+ BC cells, providing insight into the crosstalk between menin, mTORC1 and MYC in ER+ BC.
Fichier principal
Vignette du fichier
Abou Ziki et al 2022.pdf (1.03 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03757057 , version 1 (25-10-2023)

Identifiants

Citer

Razan Abou Ziki, Romain Teinturier, Yakun Luo, Catherine Cerutti, Jean-Marc Vanacker, et al.. MEN1 silencing triggers the dysregulation of mTORC1 and MYC pathways in ER+ breast cancer cells. Endocrine-Related Cancer, 2022, 29 (8), pp.451-465. ⟨10.1530/ERC-21-0337⟩. ⟨hal-03757057⟩
57 Consultations
39 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More