SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?
Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action. SOM230 inhibited mammary development in intact and hypophysectomized female rats, a process requiring IGF-I. IGF-I overcame this inhibition. SOM230 also inhibited other actions of IGF-I (inhibition of apoptosis, phosphorylation of insulin receptor substrate-1, and cell division). SOM230 did not reduce IGF-I mRNA abundance in mammary gland but did stimulate IGF binding protein 5 (IGFBP5). IGFBP5 was 3.75 times higher in mammary epithelium of SOM230 than in placebo animals (P < 0.001). Administration of IGFBP-5 also inhibited GH-induced mammary development (P < 0.001). Measurement of sstr(1-5) (somatostatin subtype receptor) by real-time RT-PCR revealed that the mammary glands had an abundance of sstr(3) and lower amounts of sstr(4) and sstr(5) but no sstr(1) or sstr(2.) That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr(2), strongly suggests that sstr(3) is at least in part mediating the effects of the SAs. We conclude that 1) SAs inhibit IGF-I action in the mammary gland through a novel nonpituitary mechanism; 2) IGFBP-5, here shown to inhibit pubertal mammary development, might mediate the effect; and 3) Measurement of available sstr receptors in the mammary gland suggests that sstr(3) mediates the SA activity, but sstr(5) is also a possible mediator.
Ruan
Weifeng
W
Neuroendocrine Unit, New York University School of Medicine, New York, New York 10016, USA.
Fahlbusch
Fabian
F
Clemmons
David R
DR
Monaco
Marie E
ME
Walden
Paul D
PD
Silva
Antonio P
AP
Schmid
Herbert A
HA
Kleinberg
David L
DL
D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D005260:Female; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D017481:Receptors, Somatostatin / Q000819:agonists*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D018975:Insulin-Like Growth Factor Binding Protein 5; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C517782:pasireotide; D015282:Octreotide