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Abstract: The human serum Sex Hormone-Binding Globulin (SHBG) plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. We here summarize data reported over the years concerning the involvement of SHBG and SHBG polymorphisms in the definition of breast cancer risk. We also report what is known about the direct action of SHBG in breast cancer cells, illustrating its interaction with these cells and the subsequent initiation of a specific intracellular pathway leading to cross-talk with the estradiol-activated pathway and, finally, to the inhibition of several effects of estradiol in breast cancer cells. In conclusion, as a result of its unique property of regulating the estrogen free fraction and cross-talking with the estradiol pathways, by inhibiting estradiol-induced breast cancer cell growth and proliferation, SHBG is associated with a reduced risk of developing the neoplasm after estrogen exposure. [Copyright &y& Elsevier]

Abstract: Sex hormone-binding globulin, the plasma carrier for sex steroids, inhibits the estradiol-induced proliferation of breast cancer cells. Estradiol induces cell proliferation triggering multiple mechanisms. Besides regulating growth factors, it activates Erk-1/-2, thus inhibiting apoptosis. In the present study, we investigated the effect of SHBG on estradiol-mediated anti-apoptotic effect in MCF-7 breast cancer cells. As expected, estradiol reduced the number of cells undergoing apoptosis. Although no modification of estradiol action was observed in cells treated contemporarily with estradiol and SHBG, pre-incubation with SHBG before estradiol treatment contrasted the anti-apoptotic effect completely. A mutant form of SHBG, lacking the O-linked oligosaccharide in Thr7, displayed no such effect. Moreover, SHBG prevented the estradiol-induced phosphorylation of Erk-1/-2, whereas it had no effect on estradiol-induced transcription. Taken together, our observations suggest that the interaction of SHBG with MCF-7 cell membranes causes inhibition of the anti-apoptotic effect of estradiol which might account for SHBG''s inhibitory effect on breast cancer cell growth. [Copyright &y& Elsevier]