Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model.

Abstract

Development of the mammary gland during puberty, pregnancy, and lactation is controlled by steroid and peptide hormones and growth factors. To determine the role of the insulin-like growth factors (IGFs) in this process we developed a transgenic model using the whey acidic protein (WAP) gene to direct expression of rat IGF-I and human IGF binding protein-3 (IGFBP-3) to mammary tissue during late pregnancy and throughout lactation.High levels of expression of transgenic IGF-I and IGFBP-3 were seen in lobular-alveolar cells by in situ hybridization. There was no obvious effect on mammary development during pregnancy and lactation; indeed, mothers were capable of nursing their pups normally and the only structural difference seen in the mammary glands at peak lactation was an overall smaller size of the alveoli. We also evaluated the role of IGF-I and IGFBP-3 in the remodeling of mammary tissue during involution. Compared with control animals, the process of involution was modified in both transgenic lines. The degree of apoptotic cells was lower in the WAP-IGF-I and WAP-BP-3 expressing mice. In addition, there was a more quiescent pattern of involution with residual lobular secretory ability and a muted host inflammatory reaction with fewer lumenal microcalcifications.These results demonstrate that IGF-I and IGFBP-3 may modulate the involutionary process of the lactating mammary gland. ( J. Clin. Invest. 1996. 97:2225-2232).

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

“…Previous results demonstrated that mammary involution was inhibited in the WAP-DES mice (Hadsell et al, 1996). In addition, inhibition of apoptosis has been demonstrated in transgenic mice which overexpress wildtype IGF-I in the mammary gland (Neuenschwander et al, 1996). Consequently, the inhibition of apoptosis observed in the mammary gland following overexpression of des(1-3)hIGF-I was not unexpected.…”

Transforming growth factor-beta induces growth inhibition and IGF-binding protein-3 production in prostatic stromal cells: abnormalities in cells cultured from benign prostatic hyperplasia tissues

“…The hypothesis commonly proposed regarding this highly regulated IGFBP secretion from cells is that local IGFBP levels govern the proliferation and survival of the cells by regulating the levels of free autocrine IGFs available to interact with the IGF receptor. Alternatively, we and others proposed that the levels of IGFBPs, particularly IGFBP-3, directly regulate cell growth and death via the recently proposed IGFBP-3 receptors/association proteins (Conover 1992, Cohen et al 1993, Oh et al 1993a, Valentinis et al 1995, Angelloz-Nicoud et al 1996, Gucev et al 1996, Lalou et al 1996, Neuenschwander et al 1996, Gill et al 1997, Karas et al 1997, Leal et al 1997, Mohseni-Zadeh & Binoux 1997, Rechler 1997.…”

“…Locally produced IGFs and IGFBPs regulate tissue growth and differentiation (Solberg & Cohen 1996). The IGFBPs are thought to modulate the action of IGFs in several ways, including an inhibitory model in which IGFBPs sequester IGFs from their receptors (Angervo et al 1991, Cohen et al 1993), an enhancing model in which IGFBPs transport IGFs to their site of action (Elgin et al 1987, Conover 1992, Neuenschwander et al 1996, or an IGF-independent model that may involve direct interaction of IGFBPs with putative IGFBP receptors (Oh et al 1993a,b, 1995, Valentinis et al 1995, Angelloz-Nicoud et al 1996, Gucev et al 1996, Lalou et al 1996, Gill et al 1997, Rechler 1997, which mediate the growth inhibitory effects of the IGFBPs. IGFBPs are regulated by various endocrine factors and are expressed in specific ontogenic patterns (Solberg & Cohen 1996).…”

“…Using a breast cancer model, Oh et al (1995) demonstrated that the stimulation of IGFBP-3 by TGF-2 is critical to TGF--induced growth inhibition, and Rajah et al (1997) showed that IGFBP-3 expression is necessary for TGF-1-induced apoptosis in a prostate cancer model. Several investigators suggest that IGFBP-3 acts directly through binding to specific cell surface receptors on susceptible cells (Conover 1992, Cohen et al 1993, Oh et al 1993a, Valentinis et al 1995, Angelloz-Nicoud et al 1996, Gucev et al 1996, Lalou et al 1996, Neuenschwander et al 1996, Gill et al 1997, Karas et al 1997, Leal et al 1997, Mohseni-Zadeh & Binoux 1997, Rechler 1997.…”

Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4

“…Normal as well as malignant growth is regulated by the endocrine action of steroid and peptide hormones which regulate the activity of locally acting factors, such as polypeptide growth factors (Dickson et al, 1991;Hennighausen and Robinson, 1998). These include TGFa and EGF, both induced by oestrogens and progesterone in some breast cancer lines, IGF, and the Wnt and FGF families of growth modulators (Bates et al, 1988;Murphy et al, 1986;Baik et al, 1998;Coleman-Krnacik and Rosen, 1994;Jackson et al, 1997;Neuenschwander et al, 1996;Gavin and McMahon, 1992). Among the growth factors we have been interested in the FGF family because alterations and/or overexpression of several of its members and their receptors have been described in human breast cancers (Penault-Llorca et al, 1995;Jaakkola et al, 1993;Payson et al, 1996).…”