Sex Hormone-Binding Globulin (SHBG), the plasma carrier for
androgens and
estradiol, inhibits the
estradiol-induced proliferation of
breast cancer cells through its membrane
receptor, cAMP, and PKA. In addition, the SHBG membrane receptor is preferentially expressed in
estrogen-dependent (ER+/PR+) breast
cancers which are also characterized by a lower proliferative rate than
tumors negative for the
SHBG receptor. A variant SHBG with a point mutation in exon 8, causing an aminoacid substitution (Asp 327-->Asn) and thus, the introduction of an additional N-glycosylation site, has been reported. In this work, the distribution of the SHBG variant was studied in 255
breast cancer patients, 32 benign mammary disease patients, and 120 healthy women. The presence of the SHBG mutation was evaluated with PCR amplification of SHBG exon 8 and Hinf I restriction fragment length polymorphism (RFLP) procedure. This technique allowed us to identify 54 SHBG variants (53 W/v and 1 v/v) in
breast cancer patients (21.2%), 5 variants (4 W/v and 1 v/v) in benign mammary disease patients (15.6%), and 14 variants (W/v) in the control group (11.6%). The results of PCR and RFLP were confirmed both by nucleotide sequence of SHBG exon 8 and western blot of the plasma SHBG. No differences in the mean plasma level of the
protein were observed in the three populations. The frequency of the SHBG variant was significantly higher in ER+/PR+
tumors and in
tumors diagnosed in patients over 50 years of age than in the control group. This observation suggests the existence of a close link between the
estrogen-dependence of
breast cancer and the additionally glycosylated SHBG, further supporting a critical role of the
protein in the
neoplasm.