Sex hormone-binding globulin, its membrane receptor, and breast cancer: a new approach to the modulation of estradiol action in neoplastic cells

The role of human Sex Hormone-Binding Globulin (SHBG), the plasma carrier o f sex steroids, and its membrane receptor, SHBG-R, in estrogen-dependent br east cancer has been investigated in our laboratory in the past few years. SHBG-R is expressed in MCF-10 A cells (not neoplastic mammary cells), MCF-7 cells (breast cancer, ER positive) and in tissue samples from patients aff ected with ER positive breast cancer, but not in estrogen-insensitive MDA-M B 231 cells. The SHBG/SHBG-R interaction, followed by the binding of estrad iol to the complex protein/receptor, causes a significant increase of the i ntracellular levels of cAMP, but does not modify the amount of estradiol en tering MCF-7 cells. The estradiol-induced proliferation of MCF-7 cells is i nhibited by SHBG, through SHBG-R, cAMP and PKA. Similarly, the proliferatio n rate of tissue samples positive for SHBG-R was significantly lower than t he proliferation rate of negative samples. SHBG and SHBG-R could thus trigg er a 'biologic' anti-estrogenic pathway. In order to get a more detailed kn owledge of this system, we first examined the frequence of the reported mut ated form of SHBG in 255 breast cancer patients. The mutated SHBG is charac terized by a point mutation (Asp 327 --> Asn) causing an additional N-glyco sylation site, which does not affect the binding of steroids to SHBG. The f requence of the mutation was significantly higher (24.5%) in estrogen-depen dent breast cancers than in healthy control subjects (11.6%). This observat ion confirms the close relationship between SHBG and estrogen-dependent bre ast cancer and suggests that the mutation could modify SHBG activity at cel l site. Lastly, the possibility of using SHBG to modulate the estradiol act ion in breast cancer was further studied by transfecting MCF-7 cells with a n expression vector carrying the SHBG cDNA (study in collaboration with G.L . Hammond), Transfected cells are able to produce significant amount of SHB G in their medium, but their SHBG-R is reduced to undetectable levels. The SHBG produced by transfected MCF-7 cells is, however, able to inhibit estra diol-induced proliferation of MCF-7 cells expressing a functional receptor, Thus, the local production of SHBG obtained with transfection could be a u seful tool to control cell growth in estrogen-dependent breast cancer. (C) 1999 Elsevier Science Ltd. All rights reserved.