Modulation of the actions of IGFs by IGFBP-5 in the mammary gland

IGFBP-5 has been associated with cell death in a number of systems; recently, the first evidence that it is involved in apoptosis of the mammary gland has been provided by studies, both in vivo and in vitro, involving the addition of exogenous IGFBP-5 and from a transgenic mouse expressing IGFBP-5 on a mammary-specific promoter. These studies have indicated that the effects are mediated in part by inhibition of IGF-signalling and involving members of the Bcl-2 family, but a role for IGF-independent effects cannot be ruled out. These IGF-independent effects involve potential interactions with components of the extracellular matrix involved in tissue remodelling such as components of the plasminogen system. In addition, intracellular events involving nuclear localisation of IGFBP-5 have been shown to have potential to inhibit cell proliferation. IGFBP-5 binds to a considerable number of molecules in the extracellular matrix, but the specific roles of these interactions in modulating its biological effects are poorly understood. The development of IGFBP-5 mutants, with differential binding characteristics, will aid in elucidating the precise roles of IGFBP-5 and potentially offer new therapeutic approaches based on IGF-independent effects in addition to its classical role of modulating IGF actions.