Sex steroid binding protein exerts a negative control on estradiol action in MCF-7 cells (human breast cancer) through cyclic adenosine 3',5'-monophosphate and protein kinase A.

Estradiol is considered to be a critical factor in the growth induction of some breast cancer cells, like MCF-7 cell line. Among other compounds involved in the control of neoplastic mammary cell growth, cAMP has been suggested, on the other hand, to exert an antiproliferative effect. Sex steroid binding protein (SBP) sex hormone binding globulin (SHBG), the plasma carrier for both androgens and estradiol, recognizes a specific receptor located on membranes of estrogen- and androgen-sensitive tissue and cultured cells (e.g. MCF-7 cell). The interaction of estradiol with the receptor-bound SBP has been reported to induce a significant accumulation of cAMP in MCF-7 cells; in addition, a negative modulation of estradiol induced proliferation of these cells has been described after treatment with SBP. We report here a more detailed observation about the effect of SBP on MCF-7 cell estradiol-induced growth as well as the possible linkage between SBP and its membrane receptor and protein kinase A activity. MCF-7 cell growth was induced by estradiol, but the effect of estradiol was completely abolished by cell treatment with both SBP and estradiol. The inhibitory effect of SBP was highly specific. Because it was suggested that SBP might act through cAMP, we investigated the effect of SBP and estradiol in cells treated with protein kinase A inhibitor peptide (6-22) amide, a specific inhibitor of the cAMP target protein kinase A. The blockade of PKA had no effect on estradiol action on cell growth but masked completely the effect of SBP because MCF-7 increased growth sustained by estradiol was fully detectable also in the presence of SBP. We also observed that MCF-7 cells treated with increasing doses of 8Br-cAMP, cAMP analog and PKA activator, showed a progressive reduction of their growth. 8Br-cAMP was also able to inhibit estradiol promotion of MCF-7 cell growth. The inhibitory effect of 8Br-cAMP on estradiol-induced proliferation was already detectable at analog concentration of 100 nM, which has been reported to be the level reached by cAMP in MCF-7 cells treated with SBP and estradiol. In conclusion, the present study strongly confirms our previous observation that SBP inhibits the estradiol induction of MCF-7 cell growth, appropriately suggesting that this SBP action, a consequence of the interaction with the receptor, is likely to be mediated by cAMP and PKA. In addition, the study implies a significant role of cAMP in the control of breast cancer cell growth.