Sex Hormone-Binding Globulin and Breast Cancer Risk

Abstract

Epidemiologic evidence supports the hypothesis that a woman's cumulative exposure to premenopausal ovarian steroids, estrogen and progesterone, contributes to the lifetime risk of developing breast cancer. A direct relationship between total endogenous levels of plasma estrogens and the incidence of breast carcinoma has not been demonstrated, however, and no substantial breast cancer risk has been consistently associated with postmenopausal estrogen replacement therapy. This paper summarizes the literature regarding the potential role of sex hormone-binding globulin (SHBG) in modifying breast cancer risk. It has been proposed that circulating levels of bio-available estrogens (ie, not bound to SHBG) might more directly reflect the risk for development of disease. Several studies have detected an association between a decreased percentage of estradiol bound to SHBG, a small increase in free estradiol, and a higher incidence of breast cancer in postmenopausal women. The physiologic significance of this increase in free estradiol, however, especially considered in the context of the relatively lower postmenopausal levels of total estradiol, is not clear. In addition to its carrier function for circulating estradiol, SHBG specifically binds to cells of steroid-responsive tissues, including breast tissue, and decreases the proliferation of some breast cancer cells through activation of cyclic adenosine monophosphate. This suggests that a decrease in the binding capacity of SHBG could potentially diminish SHBG binding to breast cell membranes and increase the rate of cellular proliferation. Oralestrogens increase plasma SHBG levels in postmenopausal women and this increase might mitigate the effect of estrogen replacement therapy on breast cancer epidemiology.