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

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 E(2.) 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 + E(2), 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 E(2) was reduced by pasireotide, as was staining intensity. These results support the concept that IGF-I inhibition, in this case by pasireotide, inhibits E(2) 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 + E(2)-induced mammary hyperplasia.