Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…Initial reports have mainly used biochemical approaches to detect interaction sites for steroid carriers in membrane preparations. Among other tissues, binding sites for SHBG have been documented in prostate, testis, epididymis and endometrium (Feldman et al, 1981;Fortunati et al, 1991;Frairia et al, 1991;Hilpert et al, 2001;Hryb et al, 1985;Krupenko et al, 1994;Porto et al, 1995), and in established cell lines such as the estrogen-dependent breast cancer cell line MCF-7 (Catalano et al, 2005;Fortunati et al, 1998;Nakhla et al, 1999;Rosner et al, 1999).…”

“…In this cell type, SHBG has been implicated in cAMP-dependent signaling of bound-estradiol (Heinlein and Chang, 2002;Kahn et al, 2008;Nakhla et al, 1999;Rosner et al, 1999). Furthermore, the carrier has been shown to antagonize estradiol-induced proliferation of these cells by inhibiting the activation of extracellular regulated kinase (ERK) -1/-2 (Catalano et al, 2005) and by regulating expression of downstream target genes involved in cell growth and Page 7 of 44 A c c e p t e d M a n u s c r i p t 7 apoptosis (Catalano et al, 2007;Fortunati and Catalano, 2006). These concepts are described in detail elsewhere in this issue.…”

Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure

“…SHBG binds to membrane of breast cancer MCF-7 cells [8,9] and, through cAMP induction and PKA activation, it inhibits the estradiol-induced cell proliferation [10]. Moreover, the protein also inhibits estradiol anti-apoptotic effect, by blocking ERK ½ activation elicited by the estradiolmembrane initiated pathway [11].…”

“…Therefore, SHBG polymorphism is likely to play some role in breast cancer, although the implication of glycosylation on SHBG function in breast cancer cells is only partially known. As far as the three glycosylation sites present in the wild type protein are concerned, it was reported that the O-glycosylation site in Thr 7 is necessary for SHBG to inhibit the effect of estradiol on both MCF-7 cell proliferation [18] and apoptosis [11], while both N-glycosylation sites (Asn 351 and Asn 367 ) are not involved. The additional carbohydrate chain in Asn 327 present in the variant D327N SHBG decreases the clearance rate of this protein [19] but no other modifications of SHBG function have been evaluated.…”

Sex hormone binding globulin in breast cancer

“…SHBG binding was demonstrated in various tissues including MCF-7 breast cancer cells and normal breast (1). In a recent study, Catalano et al (2) observed that the interaction of SHBG with MCF-7 cell membrane causes inhibition of the anti-apoptotic effect of estradiol, which might account for SHBG's inhibitory effect on breast cancer cell growth.…”