mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation
| Autor: | Rachel S. Salamon, Rose Snyder, Anya Alayev, Rafael Cuesta, Naomi S. Schwartz, Marina K. Holz, Sara Malka Berger |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Estrogen receptor mTORC1 Serine Phosphorylation ERα Reverse Transcriptase Polymerase Chain Reaction TOR Serine-Threonine Kinases Estrogen Antagonists Raptor Gene Expression Regulation Neoplastic MCF-7 Cells RNA Interference biological phenomena cell phenomena and immunity Protein Binding Signal Transduction medicine.drug medicine.medical_specialty medicine.drug_class Active Transport Cell Nucleus Breast Neoplasms P70-S6 Kinase 1 Mechanistic Target of Rapamycin Complex 1 Biology Article 03 medical and health sciences Cell Line Tumor Internal medicine Breast Cancer Genetics medicine Humans Molecular Biology PI3K/AKT/mTOR pathway Estrogen receptor beta Adaptor Proteins Signal Transducing Cell Nucleus Estrogen Receptor alpha Estrogens Regulatory-Associated Protein of mTOR Estrogen Tamoxifen HEK293 Cells 030104 developmental biology Endocrinology Microscopy Fluorescence Multiprotein Complexes Cancer research Estrogen receptor alpha |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Breast cancer is the leading cause of cancer-related deaths among women. Approximately 75% of breast cancers are estrogen receptor α (ERα) positive, underscoring the dependence of cancer cells on estrogen for growth and survival. Patients treated with endocrine therapy often develop resistance, either de novo or acquired, which in some cases is caused by aberrations within the growth factor signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) has emerged as a critical node in estrogenic signaling. We have previously shown that mTORC1 can phosphorylate and activate ERα on S167 via its effector the 40S ribosomal S6 kinase 1 (S6K1). Presently, we have uncovered a direct link between mTORC1 and ERα. We found that ERα binds to regulatory-associated protein of mTOR (Raptor) and causes it to translocate to the nucleus upon estrogen stimulation. Additionally, we identified mTOR as the kinase that phosphorylates ERα on S104/106 and activates transcription of ER target genes. Our findings show a direct link between mTORC1 and ERα, which further implicates mTORC1 signaling in the pathogenesis of ER-positive breast cancer and provides rationale for FDA-approved use of mTORC1 inhibitors in combination with endocrine agents for treatment of this disease. |
| Databáze: | OpenAIRE |
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