Dysregulation of IGF-I signaling in uterine leiomyoma.
IGF-I expression has been observed in human uterine leiomyomas. To examine whether autocrine IGF-I signaling plays a role in the growth of these tumors, we used an animal model of uterine leiomyoma (the Eker rat) to investigate regulation of IGF-I and the IGF-I receptor (IGF-IR) expression in tumors and normal myometrium. During the normal estrous cycle, myometrial IGF-I expression peaked on the day of proestrus when the rate of proliferation in this tissue is greatest. In leiomyomas, the expression of IGF-I was increased 7.5-fold compared with the age-matched normal tissue. The level of IGF-IR mRNA in both tumor and non-tumor tissues was found to inversely correlate with that of IGF-I. Changes observed in IGF-I signaling components correlated with the activation state of the signal-transducing protein insulin receptor substrate-1 (IRS-1). During diestrus and proestrus when IGF-I levels were increasing, tyrosine phosphorylation of IRS-1 was increased up to 5.7-fold in the normal myometrium relative to estrus, when IGF-I levels were the lowest. Additionally, IRS-1 phosphorylation was 4-fold greater in leiomyomas relative to age-matched normal myometrium. Autocrine stimulation of the IGF-IR may, therefore, play a role in regulating the normal growth of the myometrium, and dysregulation of IGF-I signaling could contribute to the neoplastic growth of uterine leiomyomas.
Burroughs
K D
KD
Department of Carcinogenesis, The University of Texas, MD Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Howe
S R
SR
Okubo
Y
Y
Fuchs-Young
R
R
LeRoith
D
D
Walker
C L
CL
D000818:Animals; D019898:Autocrine Communication; D015153:Blotting, Western; D002450:Cell Communication; D002455:Cell Division / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007889:Leiomyoma / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D017451:Receptors, Somatomedin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism*
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I