IGF binding proteins (IGFBPs) and regulation of breast cancer biology.

The IGFBP family comprises six proteins with high affinity for the IGFs. Changes in the balance of the components of the IGF system may contribute to the progression of breast cancer. In tumours the abundance of IGFBPs relates to the estrogen receptor status and their production in the breast is controlled by hormones, principally estrogen and progesterone. Important interactions occur between IGFBPs and key growth regulators such as TGF-beta, PTEN and EGF which are reviewed. The conflicting observations between the effects of IGFBPs on the risk of breast cancer, in particular IGFBP-3, obtained from epidemiology studies in comparison to in vivo observations are highlighted and potential explanations provided. The functional activity of IGFBPs can also be affected by proteolysis, phosphorylation and glycosylation and the implications of these are described. The IGFs are generally present at levels far in excess of that required for maximal receptor stimulation, and the IGFBPs are critical regulators of their cellular actions. IGFBPs can affect cell function in an IGF-dependent or independent manner. The key mechanisms underlying the intrinsic actions of the IGFBPs are still in debate. IGF bioactivity locally in the breast is influenced not only by local tissue expression and regulation of IGFs, IGFBPs and IGFBP proteases, but also by these factors delivered from the circulation. Finally, the therapeutic potential of IGFBPs-2 and -3 are considered together with key questions that still need to be addressed.