Effect of Sex Hormone Binding Globulin on the Development of Ovarian Cancer in a Mouse Model

Abstract

Sex hormone-binding globulin (SHBG) is the major carrier protein of testosterone and estradiol in the blood. Although studies on the role of SHBG in ovarian cancer are inconclusive, substantial evidence indicates that SHBG- steroid complexes can play a direct role in the intracellular transport of steroids to cancer cells. SHBG is synthesized in the adult liver of many species, excluding rodents. Adult mouse and rat livers do not produce SHBG, and yet most experimental models of ovarian cancer employ these species. Data reported here indicate that SHBG has a major stimulatory effect on the growth of human ovarian cancer in athymic mice. The effect is observed in subcutaneous and intraperitoneal OVCAR-3 xenografts. Tumor doubling times were 9.98±0.14 days and 17.20±0.64 days when OVCAR-3 cells were implanted with and without SHBG, respectively (P = 0.023). The magnitude of SHBG effect depended on the age of mice and it was most prominent in the development of intraperitoneal solid tumor deposits. Levels of circulating CA-125 were also age- and tumor size-dependent. Biodistribution studies of 125 I-SHBG indicated a prolonged retention of the protein in solid tumor deposits. Estimated half-lives of 125 I-SHBG were 2.3� longer in solid tumors as compared to nonadherent cancer cells in the peritoneal lavage. The normal tissue distribution of 125 I-SHBG was similar in control and OVCAR-3-bearing mice. These data suggest that currently used models of ovarian cancer in mice, including carcinogenesis and drug evaluation studies, are imperfect because of the lack of SHBG production in these species.