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SOM230 Inhibits Insulin-Like Growth Factor-I Action in Mammary Gland Development by Pituitary Independent Mechanism: Mediated through Somatostatin Subtype Receptor 3?

Neuroendocrine Unit (W.R., F.F., D.L.K.), Departments of Medicine (W.R., F.F., D.L.K.), Physiology (M.E.M.), Urology (P.D.W.), and Biochemistry (P.D.W.), New York University School of Medicine, New York, New York 10016; Division of Endocrinology (D.R.C.), University of North Carolina, Chapel Hill, North Carolina 27599; and Novartis Institutes for Biomedical Research (A.P.S., H.A.S.), Department of Oncology, CH-4057 Basel, Switzerland

Address all correspondence and requests for reprints to: David L. Kleinberg, Neuroendocrine Unit, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: david.kleinberg{at}med.nyu.edu.

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 sstr₃ and lower amounts of sstr₄ and sstr₅ but no sstr₁ or sstr_2. That mammary development was also inhibited to a lesser degree than SOM230 by octreotide, whose main action is through sstr₂, strongly suggests that sstr₃ 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 sstr₃ mediates the SA activity, but sstr₅ is also a possible mediator.

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