mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation.
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. In addition, 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.
Mesh Terms:
Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, Cell Line, Tumor, Cell Nucleus, Estrogen Antagonists, Estrogen Receptor alpha, Estrogens, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, MCF-7 Cells, Mechanistic Target of Rapamycin Complex 1, Microscopy, Fluorescence, Multiprotein Complexes, Phosphorylation, Protein Binding, RNA Interference, Regulatory-Associated Protein of mTOR, Reverse Transcriptase Polymerase Chain Reaction, Serine, Signal Transduction, TOR Serine-Threonine Kinases, Tamoxifen
Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, Cell Line, Tumor, Cell Nucleus, Estrogen Antagonists, Estrogen Receptor alpha, Estrogens, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, MCF-7 Cells, Mechanistic Target of Rapamycin Complex 1, Microscopy, Fluorescence, Multiprotein Complexes, Phosphorylation, Protein Binding, RNA Interference, Regulatory-Associated Protein of mTOR, Reverse Transcriptase Polymerase Chain Reaction, Serine, Signal Transduction, TOR Serine-Threonine Kinases, Tamoxifen
Oncogene
Date: Jul. 07, 2016
PubMed ID: 26522726
View in: Pubmed Google Scholar
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