Control of mammary involution by insulin-like growth factor binding proteins: role of prolactin

The insulin-like growth factor binding proteins (IGFBPs) constitute a famil y of proteins which modulate the activity of the IGFs. IGF-I is an importan t survival factor for mammary epithelial cells and overexpression of IGF-I in the mammary glands of lactating mice can delay involution. We have shown that the mouse, rat and pig mammary gland produces IGFBP-5 during the earl y stage of mammary involution and we proposed that the function of this bin ding protein is to inhibit IGF-mediated cell survival and thereby to induce apoptotic cell death. Prolactin is a potent inhibitor of IGFBP-5 expressio n and we believe this is an important aspect of its anti-apoptotic effect. Subsequently we have shown that over expression of IGFBP-5 in the mammary g land of lactating mice leads to impaired milk production, with a reduction in the number of mammary epithelial cells. The precise mechanism by which t his occurs is currently under investigation. In ovine and bovine mammary gl and IGFBP-5 is not yet implicated although IGFBP-3 concentrations increase in cows during mammary involution and it is possible that IGFBP-3 serves th is function in ruminants. In addition, the IGFBPs have been shown to intera ct with several proteins present in milk including alpha (s2)-casein, lacto ferrin and transferrin. These interactions implicate the IGFBPs in the regu lation of plasminogen activation since plasminogen and t-PA also bind to al pha (s2)-casein. This is a key process in tissue remodelling although, at t he moment, no unifying hypothesis exists with regard to the nature of these interactions. Some studies have suggested that these interactions of IGFBP s with milk proteins lead to increased growth factor availability whereas o thers suggest that this serves to function as a means of sequestering IGF-I from its receptor. Whatever their role, it is clear that the IGFBPs play a n important role in mammary gland function. (C) 2001 Elsevier Science B.V. All rights reserved.