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.

Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model

“…A recent study demonstrated that SOM230 has a proapoptotic effect on rat mammary gland hyperplastic cells, mediated through sstr3 21 . Analogously, our study demonstrated a significant increase in apoptotic events as evidenced by a TUNEL assay, which demonstrated increased DNA fragmentation in the pancreata of mice treated with SOM230 vs. the pancreata of mice treated with PBS.…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…Indirectly targeting IGF1R signaling can also be achieved by using somatostatin or its analogues such as pasireotide (SOM230), which is approved as a therapy in the United States and Europe for conditions including Cushing's disease and acromegaly, and it acts to reduce growth hormone production and consequently IGF-1 production and signaling (Kleinberg et al 2011, Lewis et al 2014. In another indirect approach, metformin, a standard treatment for type 2 diabetes, is shown to inhibit crosstalk between InsR/IGF1R and EGFR and as a result has indirect effects on IGF-1 signaling (Rozengurt et al 2010, Liu et al 2011.…”

Potential Mechanisms underlying the Protective Effect of Pregnancy against Breast Cancer: A Focus on the IGF Pathway

“…Tamoxifen therapy causes unpleasant side effects leading to a drastic diminishment in its use in more recent years (102, 103). There are investigations into IGF1R inhibitors as preventative therapies, but these are toxic as well and therefore again only will be helpful in high-risk women (104–106). With the age of FFTB rising and the lack of preventative options, discovering the most important mechanisms underlying the protective effect of an early FFTB is imperative to developing prevention strategies for young healthy women (11, 107).…”