Sex hormone-binding globulin: not only a transport protein. What news is around the corner?

The plasma Sex Hormone-Binding Globulin (SHBG) transports androgens and estradiol in the blood and regulates their bioavailable fraction and access to target cells. The recent advances in the knowledge of its structure and gene expression, and notabily the demonstration of a specific receptor (SHBG-R) located on membranes of sex steroid responsive cells, gave support to the thesis that SHBG has much more sophisticated functions at cell site. In particular, the receptor-mediated action of SHBG, which uses as a second messenger cAMP, has been linked to the effects of androgens and estradiol. It is conceivable that the SHBG/SHBG-R system works as an additional control mechanism which inhibits or amplifies the effects of DHT and estradiol in cells. In the prostate, it has been suggested that the estradiol-activated SHBG/SHBG-R complex cross-talks with the androgen receptor, and is able to activate AR even in the absence of DHT. Of great interest, for its potential clinical applications, is the observation that in estrogen-dependent breast cancer SHBG, through SHBG-R, cAMP and PKA, specifically inhibits the estradiol-induction of cell proliferation. This anti-proliferative, anti-estrogenic effect of human SHBG has not only increased and continues to increase our understanding of the molecular mechanisms involved in the biology of breast cancer, but could also be exploited as a future therapeutic strategy in the managing of estrogen-dependent tumours.