Insulin-like growth factor binding proteins and mammary gland development

Abstract

Mammary gland development is dependent upon insulin-like growth factors (IGFs) as survival factors. The actions of the IGFs are modulated by a family of IGF-binding proteins (IGFBP1-6). Expression of the IGFBPs is both time-dependent and cell-specific during both the developmental phases and the involution of the mammary gland. Although studied extensively in vitro, understanding the roles of IGFBPs in vivo has been difficult, largely due to the fact that IGFBP knock-out mice have no dramatic phenotypes. This review examines the evidence from in vitro studies and the attempts to examine in vivo actions utilising models with IGFBP deficiency or over-expression. In vitro studies demonstrate that IGFBPs can act by inhibition of the survival effects of IGFs, as well as by enhancing the effects of IGFs. Because the IGFBPs are found associated with the extracellular matrix, a role for IGFBPs as a reservoir of IGFs or, alternatively as a potential barrier to IGFs, thereby restricting their entry into particular tissues or cellular compartments was postulated. We also provide evidence with respect to the IGF-independent actions of the IGFBPs which include receptors, nuclear localization, and interaction with the extracellular matrix and cell surface proteins including integrins. We believe that recent findings place some of the IGFBPs in a larger family of extracellular proteins, the secreted cysteine-rich protein (CCN) family, which have similar structural domains (involved in binding to IGFs, extracellular matrix and integrins) and are heavily implicated in tissue re-modeling and morphogenesis.

Perlecan Diversely Regulates the Migration and Proliferation of Distinct Cell Types in vitro

“…Means ± SD (n = 3) of at least three independent experiments. * p < 0.05; * * p < 0.01; * * * p < 0.001. it at high concentrations [Chen et al, 2001;Belleudi et al, 2007;Sureshbabu et al, 2011].…”

“…Interestingly, the proliferation of low-density-cultured pre-adipocytes was promoted by endogenous perlecan, but inhibited by supplementation with exogenous perlecan. In addition to perlecan, heparin, insulin-like growth factor-binding protein and fibroblast growth factor-binding protein are known to interact with extracellular signaling molecules to regulate their binding to cognate receptors [Spivak-Kroizman et al, 1994;Abuharbeid et al, 2006;Sureshbabu et al, 2011]. These molecules play a dual role in the presentation of extracellular signaling molecules.…”

Temporal Trends in the Inflammatory Cytokine Profile of Human Breastmilk

“…37 Finally, expression of IGFBP-1 and TIMP-2 has been measured in human breastmilk, and both cytokines have previously been found to decrease in level during lactation, 38,39 with the IGFBP-1 level decreasing over the first 3 months postpartum before stabilizing through Month 9 of lactation. 38 It is not yet known how expression of these cytokines may be interrelated during lactation, although their known associations with breast involution, inflammation, and breast cancer suggest that these nine cytokines may be strong candidates for breast microenvironment biomarkers. Future experimental work is needed to establish the biological significance of these cytokines at the concentrations found in human breastmilk.…”

Apoptosis and Clearance of the Secretory Mammary Epithelium

“…Overexpression of IGF-1 in the mouse mammary gland delayed post-lactational involution, suggesting that suppression of IGF-mediated cell survival is required for apoptosis to occur, and supporting the idea that PI3K signaling must be interrupted to initiate post-lactational apoptosis [77]. IGF-1 bio-availability is tightly controlled by IGF binding proteins (IGFBPs), which can sequester IGFs in the extracellular microenvironment of the mammary epithelium [78]. Consistent with the ability of IGF-1 to interfere with post-lactational cell death, one of the earliest transcriptional events during post-lactational involution is the upregulation of IGFBP-2 mRNA (4-fold), IGFBP-4 (6-fold) and IGFBP-5 mRNA (50-fold) [79].…”

“…An IGF-1 analogue which binds weakly to IGFBP-5 partially overcame IGFBP-5-induced cell death during post-lactational involution, suggesting that IGFBP-5 was acting, at least in part, by inhibiting IGF action. Conversely, Igfbp5 null mammary glands exhibit delayed post-lactational apoptosis [78].…”