title: Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia.
abstract: Mammary hyperplasia increases breast cancer risk. Tamoxifen prevents breast cancer in women with atypical hyperplasia, but has serious side effects. As estradiol action requires IGF-I, direct inhibition of IGF-I action theoretically might be an efficacious alternative to tamoxifen. After hypophysectomy and oophorectomy, 21-day-old female rats were treated with GH and E₂. After 7 days all terminal end buds (TEBs) and 75% of ducts became hyperplastic. Co-treatment with pasireotide, a somatostatin analog that blocks GH secretion and IGF-I action in the mammary gland, prevented hormone-induced hyperplasia. The number and size of TEBs and moderately or floridly hyperplastic ducts was reduced by pasireotide (P < 0.01). In contrast, the same concentration of octreotide, which has a more selective somatostatin receptor subtype binding profile, was less effective than pasireotide. Tamoxifen inhibited hyperplasia when used alone with GH + E₂, but did not add to the inhibitory effect of pasireotide when the two treatments were combined. Both pasireotide and tamoxifen acted via the IGF-I receptor signaling pathway and both were found to inhibit mammary cell proliferation and stimulate apoptosis. The number of epithelial cells expressing phosphorylated insulin receptor substrate (IRS)-1 in response to GH and E₂ was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E₂ and GH-induced mammary hyperplasia. As tamoxifen did not further increase the inhibitory effect of pasireotide, the peptide appears to be at least as effective as tamoxifen in preventing GH + E₂-induced mammary hyperplasia.
authors.affiliation: The Bunnie Joan Sachs Laboratory and Neuroendocrine Unit, Department of Medicine (Division of Endocrinology), New York University School of Medicine, New York, NY, USA. David.Kleinberg@nyumc.org
authors.forename: David L
authors.initials: DL
authors.lastname: Kleinberg
authors.forename: Pietro
authors.initials: P
authors.lastname: Ameri
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
mesh_terms: D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D006965:Hyperplasia / Q000139:chemically induced / Q000517:prevention & control*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D055504:Insulin Receptor Substrate Proteins; D013629:Tamoxifen; D004958:Estradiol; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C517782:pasireotide