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Pasireotide, an IGF-1 action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia

Kleinberg, David L and Ameri, Pietro and Singh, Baljit (2011) Pasireotide, an IGF-1 action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia. Pituary, 14 (1). pp. 44-52. ISSN 1386-341X

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, with 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 act 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.

Item Type: Article
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Keywords: SOM230, IGF-1 inhibitors, tamoxifen
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3512

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