William Rosner

Sex hormone-binding globulin influences gene expression of LNCaP and MCF-7 cells in response to androgen and estrogen treatment.

Sex hormone-binding globulin (SHBG), a plasma protein that binds androgens and estrogens, also participates in the initial steps of a membrane-based steroid signaling pathway in human prostate and breast. We have recently shown that SHBG is expressed at the mRNA and protein levels in the prostate and breast. In this study, we addressed whether locally expressed SHBG: (1) Functions to regulate activation of membrane-based steroid signaling and (2) influences activation of the androgen (AR) and estrogen (ER) receptors. Using microarray analysis, we identified specific genes that are influenced by SHBG expression in LNCaP and MCF-7 cells in a manner consistent with each of these properties. These findings suggest that locally expressed SHBG can play a functional role in the steroid responsiveness of prostate and breast cells through multiple signaling pathways and that perturbations in local SHBG expression could contribute to prostate and breast cancer.

Immunohistochemical and In-Situ Detection of Sex Hormone-binding Globulin (SHBG) Expression in Breast and Prostate Cancer: Implications for Hormone Regulation

Sex Hormone Binding Globulin (SHBG), in addition to regulating free concentrations of steroid sex hormones in plasma, also participates in membrane-based steroid signaling in breast and prostate cells. In this study, we address whether the breast and prostate can synthesize their own SHBG. SHBG mRNA and protein were detected in human breast and prostate cancer cell lines, as well as in normal and cancerous breast and prostate tissue where it was prominent in epithelial cells. In cultured human LNCaP prostate cancer cells, SHBG was found both in the cytoplasm, and on the outer cell membrane where it was presumably bound to its high affinity receptor (RSHBG). When LNCaP cells were treated with 2-methoxyestradiol (2MeOE2), an antagonist of SHBG binding to RSHBG, membrane-associated SHBG was eliminated. These results demonstrate that the breast and prostate can synthesize SHBG locally, and that SHBG can bind to, and perhaps participate in autocrine and/or paracrine signaling through RSHBG. Therefore, perturbations in SHBG expression in breast and prostate tumors may affect the regulation of steroid signaling through RSHBG and target SHBG-mediated biologic properties at the cellular level.

Sex Hormone-Binding Globulin as a Modulator of the Prostate “Androgenome”

Sex hormone-binding globulin (SHBG) is a sex steroid binding protein, originally described in humans as the major binding protein for estrogens and androgens in plasma (Anderson, 1974; Avvakumov, et al, 2010). By governing equilibrium conditions in plasma between bound and free sex steroids, SHBG regulates the availability of the latter to hormonally responsive tissues. Along with regulating free steroid concentrations in plasma, it is increasingly evident that SHBG also participates in other biological processes. These include, but are not limited toactivation of a rapid, membrane based steroid signaling pathway in tissues such as the prostate and breast (Rosner et al, 2010); spermatogenesis (Selva and Hammond, 2006); and a yet to be determined consequence of co-localization with oxytosin in brain cells (Caldwell et al, 2006). Plasma based SHBG is extensively studied, especially in the context of its regulation of free steroid concentrations and epidemiologic associations. The origin of plasma SHBG is, for all intents and purposes, the liver (Khan et al, 1981; Pugeat et al, 2010) (a differentially glycosylated isoform, androgen binding protein (ABP) is synthesized in the testis (Vigersky et al, 1976)). However, we now know that SHBG is also synthesized, albeit to a much lesser degree, in certain hormonally responsive tissues (Kahn et al, 2002). Early studies demonstrated immunoreactive SHBG in the prostate and breast (Bordin & Petra 1980; Tardivel-Lacombe et al, 1984; Sinnecker et al, 1988; 1990; Meyer et al, 1994; Germain et al, 1997), though its origin (local synthesis vs. import from plasma) was unclear. Other studies demonstrated SHBG mRNA in certain nonhepatic tissues (Larrea et al, 1993; Misao et al, 1994; 1997; Moore et al, 1996; Murayama et al, 1999), and one reported both SHBG protein and mRNA together in fallopian tube tissue (Noe, 1999). In 2002, we reported that human prostate tissue expresses both SHBG mRNA and protein, as do prostate cancer cell lines (Hryb et al, 2002), suggesting that SHBG is indeed locally