Model for SHBG-mediated signaling. The plasma membrane binding site for SHBG is preferentially expressed in ER+ cells with a reduced proliferative index [2-4]. SHBG-R only binds steroid-free or unliganded SHBG. Following binding of unliganded SHBG to SHBG-R on the cell membrane, E2 binds to the SHBG–SHBG-R complex, thereby activating it. Activation induces the synthesis of cAMP, which, in turn, triggers downstream signaling via PKA [2-4]. The biological outcome of this signaling pathway in cells of the human breast carcinoma cell line MCF-7 is decreased E2-mediated cell growth.