title: Loss of inhibitory insulin receptor substrate-1 phosphorylation is an early event in mammalian target of rapamycin-dependent endometrial hyperplasia and carcinoma.
abstract: Insulin-like growth factor-I receptor signaling contributes to the development of endometrial hyperplasia, the precursor to endometrioid-type endometrial carcinoma, in humans and in rodent models. This pathway is under both positive and negative regulation, including S6 kinase (S6K) phosphorylation of insulin receptor substrate-1 (IRS-1) at S636/639, which occurs downstream of mammalian target of rapamycin (mTOR) activation to inhibit this adapter protein. We observed activation of mTOR with a high frequency in human endometrial hyperplasia and carcinoma, but an absence of IRS-1 phosphorylation, despite high levels of activated S6K. To explore when during disease progression mammalian target of rapamycin (mTOR) activation and loss of negative feedback to IRS-1 occurred, we used the Eker rat (Tsc2(Ek/+)) model, where endometrial hyperplasia develops as a result of loss of Tsc2, a "gatekeeper" for mTOR. We observed mTOR activation early in progression in hyperplasias and in some histologically normal epithelial cells, suggesting that event(s) in addition to loss of Tsc2 were required for progression to hyperplasia. In contrast, whereas IRS-1 S636/639 phosphorylation was observed in normal epithelium, it was absent from all hyperplasias, indicating loss of IRS-1 inhibition by S6K occurred during progression to hyperplasia. Treatment with a mTOR inhibitor (WAY-129327) significantly decreased hyperplasia incidence and proliferative indices. Because progression from normal epithelium to carcinoma proceeds through endometrial hyperplasia, these data suggest a progression sequence where activation of mTOR is followed by loss of negative feedback to IRS-1 during the initial stages of development of this disease.
authors.affiliation: Department of Pathology, Science Park Research Division, The University of Texas M.D. Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harris
authors.forename: Judy S
authors.initials: JS
authors.lastname: Crabtree
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004714:Endometrial Hyperplasia / Q000378:metabolism* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
chemical_list: D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C546845:mTOR protein, rat; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases