title: mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation.
abstract: 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.
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Alayev
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Salamon
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Berger
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Schwartz
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cuesta
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Snyder
authors.affiliation: Department of Biology, Yeshiva University, New York, NY, USA.|Department of Molecular Pharmacology and Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Holz
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D000076223:Regulatory-Associated Protein of mTOR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D046912:Multiprotein Complexes; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D013629:Tamoxifen; D012694:Serine; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases