Insulin-Like Growth Factor Binding Proteins: IGF-Dependent and -Independent Effects in the Mammary Gland

The insulin-like growth factor binding proteins (IGFBPs)3 are a family of proteins which bindto the IGFs with high affinity. Their expression within the mammary gland is species specific;it has thus been difficult to determine the biological roles of these binding proteins duringlactation. In this article we propose a role for IGFBP-5 in the mammary gland involving theinitiation of apoptosis induced by sequestration of IGF-1, an important survival factor for themammary gland. We have shown that this binding protein retains its high affinity for IGF-1and that it is present in extremely high concentrations compared with the growth factor. Theseobservations make it likely that IGFBP-5 is capable of preventing interaction of IGF-1 withits receptor on the epithelial cells synthesizing milk. We have also demonstrated thatIGFBP-5 interacts with αs2-casein and that this interaction implicates it in the regulation of plasminogenactivation in the mammary gland. The generation of plasmin is a key initiating event in theremodeling of the extracellular matrix during mammary involution. As such, IGFBP-5 mayplay a key role in coordinating cell death and tissue remodeling processes. Many of themolecules involved in embryological development are also expressed in the developing andinvoluting mammary gland. We believe that our studies may offer mechanistic explanationsfor apoptotic events in a wide variety of tissues. We have recently shown that IGFBP-5 isapoptotic in the chick embryonic limb bud, adding further support to our belief thatIGFBP-5 serves this function in the mammary gland. We hope to be able to explore the role of thisbinding protein in the mammary gland with a transgenic mouse model expressing IGFBP-5on the β-lactoglobulin promoter.