Targeted expression of des(1-3) human insulin-like growth factor I in transgenic mice influences mammary gland development and IGF-binding protein expression.

Abstract

To test the hypothesis that insulin-like growth factor I (IGF-I) regulates mammary gland development and lactation, the expression of both human (h) IGF-I and des(1-3)hIGF-I was targeted to the mammary gland in transgenic mice using a novel exon replacement strategy and the rat whey acidic protein (rWAP) gene regulatory sequences. Both transgenes expressed a 0.7-kilobase messenger RNA (mRNA). The abundance of WAP-IGE-I and WAP-DES mRNA on day 10 of lactation ranged from 0.2-1.0% and 0.2-13% of the endogenous mouse WAP mRNA, respectively. For WAP-DES mice, transgene expression was greatest from midpregnancy throughout lactation. Western blot analysis showed the presence of correctly processed hIGF-I in milk from these transgenic mice. This hIGF-I was capable of stimulating protein synthesis in cultured rat L6 myoblasts. Ligand blotting indicated changes in mammary gland secretion of IGFBP in response to WAP-DES expression. Histological analysis of mammary tissue from mice overexpressing des(1-3)hIGF-I showed incomplete mammary involution, ductile hypertrophy, and loss of secretory lobules associated with increased deposition of collagen. These changes are believed to occur through autocrine and paracrine effects of des(1-3)-hIGF-I on both epithelial and stromal cells.

Glycemic index in chronic disease: a review

“…Transgenic mice overexpressing growth hormone have a higher frequency of breast cancer (Bates et al, 1995;Hadsell et al, 1996) and disruption of the IGF-1 gene seems to prevent breast tumor formation by viral oncogens (Sell et al, 1993). Human mechanistic studies of the effect of estrogen antagonist drugs on breast carcinogenesis have shown a direct link with IGF-1.…”

The GH–IGF-I axis and breast cancer

“…Early studies revealed a positive correlation between the activity of the GH-IGF-1 axis and development of breast tumors in mice 71 . Subsequently, transgenic mice that over express growth hormone have been shown to exhibit both mammary gland epithelial cell hyperplasia 72 and have an increased frequency of mammary tumours, as do mice with over expression of IGF-1R agonists 73 . In contrast, ductal hypoplasia is seen in transgenic animals that over express a GH antagonist 74 .…”

Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis

“…The presence of mammary tumors and hyperplasias, coupled with our previous observation (Hadsell et al, 1996) of inhibited mammary involution in the WAP-DES mice, led us to examine the e ects of WAP-DES expression on apoptosis and DNA synthesis in the mammary gland. The mammary gland gradually begins to involute between days 15 and 22 of lactation (Quarrie et al, 1996).…”

“…Previous studies (Hadsell et al, 1996) in our laboratory have shown that lactation-dependent, mammary-speci®c overexpression of a potent IGF-I analog with reduced a nity for IGF binding proteins, des(1-3)hIGF-I (WAP-DES), inhibits normal mammary gland involution. At the time of that study, a small number of WAP-DES mice had been observed to develop palpable mammary tumors.…”