Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming
| Autor: | Rezina Arju, Abhilash Gadi, Amandine Alard, Sofia Bakogianni, Shah Giashuddin, Phillip A. Geter, Jacqueline Bromberg, Robert J. Schneider, Amanda Ernlund |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Antineoplastic Agents Hormonal medicine.drug_class Estrogen receptor Breast Neoplasms Biology Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor Genetics medicine Gene silencing Humans RNA Messenger Phosphorylation skin and connective tissue diseases PI3K/AKT/mTOR pathway EIF4E Estrogen Antagonists Intracellular Signaling Peptides and Proteins medicine.disease Tamoxifen 030104 developmental biology Eukaryotic Initiation Factor-4E Estrogen Drug Resistance Neoplasm 030220 oncology & carcinogenesis Protein Biosynthesis Cancer research Female hormones hormone substitutes and hormone antagonists Developmental Biology medicine.drug Research Paper |
| Zdroj: | Genesdevelopment. 31(22) |
| ISSN: | 1549-5477 |
| Popis: | The majority of breast cancers expresses the estrogen receptor (ER+) and is treated with anti-estrogen therapies, particularly tamoxifen in premenopausal women. However, tamoxifen resistance is responsible for a large proportion of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen-sensitive and tamoxifen-resistant breast cancer cells, a tamoxifen-resistant patient-derived xenograft model, patient tumor tissues, and genome-wide transcription and translation studies, we show that tamoxifen resistance involves selective mRNA translational reprogramming to an anti-estrogen state by Runx2 and other mRNAs. Tamoxifen-resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR and to require phosphorylation of eIF4E at Ser209 by increased MNK activity. Resensitization to tamoxifen is restored only by reducing eIF4E expression or mTOR activity and also blocking MNK1 phosphorylation of eIF4E. mRNAs specifically translationally up-regulated with tamoxifen resistance include Runx2, which inhibits ER signaling and estrogen responses and promotes breast cancer metastasis. Silencing Runx2 significantly restores tamoxifen sensitivity. Tamoxifen-resistant but not tamoxifen-sensitive patient ER+ breast cancer specimens also demonstrate strongly increased MNK phosphorylation of eIF4E. eIF4E levels, availability, and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through selective mRNA translational reprogramming |
| Databáze: | OpenAIRE |
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